Bis-heteroaryl derivatives as modulators of protein aggregation

ABSTRACT

The present invention relates to certain bis-heteroaryl compounds, pharmaceutical compositions containing them, and methods of using them, including methods for preventing, reversing, slowing, or inhibiting protein aggregation, and methods of treating diseases that are associated with protein aggregation, including neurodegenerative diseases such as Parkinson&#39;s disease, Alzheimer&#39;s disease, Lewy body disease, Parkinson&#39;s disease with dementia, fronto-temporal dementia, Huntington&#39;s Disease, amyotrophic lateral sclerosis, and multiple system atrophy, and cancer including melanoma.

TECHNICAL FIELD

The present invention relates to certain bis-heteroaryl derivatives,pharmaceutical compositions containing them, and methods of using them,including methods for preventing, reversing, slowing, or inhibitingprotein aggregation, and methods of treating diseases that areassociated with protein aggregation, including neurodegenerativediseases such as Parkinson's disease, Alzheimer's disease, Lewy bodydisease, Parkinson's disease with dementia, fronto-temporal dementia,Huntington's Disease, amyotrophic lateral sclerosis, and multiple systematrophy, and cancer including melanoma.

BACKGROUND

Neurodegenerative disorders of the aging population such as Alzheimer'sdisease (AD), Parkinson's disease (PD), and fronto-temporal dementia(FTD), affect over 20 million people in the United States and EuropeanUnion alone and rank among the top causes of death for the elderly. Acommon feature among these neurological disorders is the chronicaccumulation of proteins into neurotoxic aggregates. Each disease ischaracterized by the specific neuronal populations that are affected,the particular protein aggregates that are involved, and the clinicalfeatures that result from the neuronal degeneration.

Studies suggest that the initial stages of protein aggregation involvemutation or post-translational modification (e.g., nitrosilation,oxidation) of the target protein, which then adopts an abnormalconformation that facilitates interactions with similarly misfoldedproteins. The abnormal proteins then aggregate to form dimers, trimers,and higher-order multimers, also termed “soluble oligomers,” which maydisrupt synaptic function. Additionally, the aggregates may then anchorin the cell membrane and form globular oligomers (which in turn can formpores in the membrane) and/or protofibrils or fibrils. These larger,insoluble fibrils may function as reservoirs of the bioactive oligomers.

Diverse lines of evidence support the notion that the progressiveaccumulation of protein aggregates is causally involved in thepathogenesis of neurodegenerative diseases. A number of other proteinsmay accumulate in the brains of patients with neurodegeneration, such asα-synuclein, Aβ protein, Tau, and TDP43. The cognitive impairment ofthese patients is closely associated with synaptic loss in the neocortexand limbic systems, and increasing levels of protein aggregates maycontribute to this synaptic loss. Much research is focused on detailingthe mechanisms through which accumulation of α-synuclein and otheramyloid precursor protein (APP) metabolites contributes to synapticdamage and neurodegeneration. Many studies support the hypothesis thatformation of small aggregates, also known as oligomers, plays a majorrole in neurotoxicity. These peptide oligomers can organize into dimers,trimers, tetramers, pentamers, and other higher order arrays that canform annular structures. High levels of such oligomers are predictive ofdementia and synaptic loss in patients. Because evidence indicates theoligomers rather than smaller precursor fibrils are the toxic species,compounds that target these early aggregation processes in a specificmanner would be useful as potential new therapies for PD, AD and relatedconditions.

Various neurodegenerative diseases involve the accumulation ofneurotoxic protein-based aggregates. In idiopathic Parkinson's disease(IPD), dementia with Lewy bodies (LBD), Parkinson's disease withdementia (PDD), and multiple system atrophy (MSA), the neurotoxicaggregates are composed of α-synuclein (SYN), which is a synapticprotein that is intracellular under normal conditions. In FTD andamyotrophic lateral sclerosis (ALS), neurotoxic aggregates originatefrom other intracellular proteins such as tau, TDP-43, or SOD1. Forcertain diseases, such as AD, SYN aggregates with the primary protein(e.g., Aβ protein). In Huntington's Disease, aggregates form from thecleavage products of Htt proteins.

Accumulation of α-synuclein has also been implicated in cancer, inparticular, in melanoma cancer cells. Pan et al., PLoS One 2012, 7(9),e45183. Thus, compounds that inhibit such accumulation may prove usefulin treatment of various cancers, including melanoma.

Two mechanisms are implicated in these protein aggregation processes. Inthe first, the misfolded and/or aggregated proteins anchor to thevarious cell membrane structures. Binding of the misfolded or aggregatedmolecules to the plasma membrane or the membranes of organelles (e.g.,mitochondria or lysosomes) may interfere with protein transcription,autophagy, mitochondrial function, and pore formation. By way ofexample, neurotoxic SYN aggregates and interacts with lipids in cellmembranes by a specific portion of the c-terminal region of thesynuclein protein. Compounds that bind to this region can inhibitprotein-protein or protein-lipid interactions and can therefore be usedto block neurotoxic oligomerization of SYN or other proteins and theirinteractions with membranes. In the second process, aggregated proteinis released from the anchored subunit and propagates to adjacent cells.This cell-to-cell propagation of toxic protein aggregates may thenunderlie the anatomic progression of neurodegeneration and worsening ofsymptoms. Small molecule drugs that interact with the target proteinsmay limit release and/or propagation, and therefore reduce theneurotoxic effects of aggregated proteins.

Compounds that are inhibitors of protein aggregation are described inPCT Publ. Nos. WO2011/084642, WO2013/148365, WO2013/134371,WO2014/014937, and WO2015/116663, and in U.S. Pat. No. 9,284,309.Additional compounds are described in U.S. Pat. No. 8,846,682. Indoleamide derivatives are described in PCT Publ. No. WO2010/142801.

There remains a need for inhibitors of protein aggregation withdesirable pharmaceutical properties. Certain bis-heteroaryl compoundshave been found in the context of this invention to have proteinaggregation modulating activity.

SUMMARY OF THE INVENTION

In one aspect, the invention relates to a chemical entity of thefollowing Formula (IA):

wherein

-   B is a 9- or 10-membered heteroaryl, or a 5- or 6-membered    heterocycloalkyl, each unsubstituted or substituted with —(R¹)_(m);    -   wherein m is 0, 1, or 2; and    -   each R¹ is independently C₁₋₄alkyl (optionally substituted with        one or more halo or —OC₁₋₄alkyl groups), halo, —OH, or        —OC₁₋₄alkyl;-   R² is H, C₁₋₅alkyl (unsubstituted or substituted with one or more    halo substituents), —OC₁₋₄alkyl, or —SC₁₋₄alkyl, or an aryl,    monocyclic cycloalkyl, or —C₁₋₄alkyl-(monocyclic cycloalkyl) group,    wherein each aryl or cycloalkyl is unsubstituted or substituted with    halo, C₁₋₄alkyl, or halo-C₁₋₄alkyl;-   A is a 5-membered heteroaryl ring;-   Y is absent or is C₁₋₄alkylene; and-   when Y is absent or is C₁₋₄alkylene, R³ and R⁴ taken together with    the nitrogen to which they are attached form a monocyclic or    bicyclic heterocycloalkyl or

each unsubstituted or substituted with one or more R^(g) substituents;

-   -   wherein each R^(g) substituent is independently C₁₋₄alkyl        (unsubstituted or substituted with one or more C₁₋₄alkoxy,        halo-C₁₋₄alkoxy, or halo groups), C₃₋₇cycloalkyl, C₁₋₄alkoxy,        halo-C₁₋₄alkoxy, or halo;

-   or, when Y is C₁₋₄alkylene, R³ and Y taken together with the    nitrogen to which R³ is attached form a monocyclic or bicyclic    heterocycloalkyl ring, which ring is unsubstituted or substituted    with C₁₋₄alkyl or halo; and R⁴ is H or C₁₋₄alkyl; and

-   R⁵ is H or C₁₋₄alkyl;

-   or a pharmaceutically acceptable salt thereof.

In one aspect, the invention relates to a chemical entity of thefollowing Formula (I):

wherein

-   B is a 9- or 10-membered heteroaryl, or a 5- or 6-membered    heterocycloalkyl, each unsubstituted or substituted with —(R¹)_(m);    -   wherein m is 0, 1, or 2; and    -   each R¹ is independently C₁₋₄alkyl (optionally substituted with        one or more halo or —OC₁₋₄alkyl groups), halo, —OH, or        —OC₁₋₄alkyl;-   R² is H, C₁₋₅alkyl (unsubstituted or substituted with one or more    halo substituents), —OC₁₋₄alkyl, or —SC₁₋₄alkyl, or an aryl,    monocyclic cycloalkyl, or —C₁₋₄alkyl-(monocyclic cycloalkyl) group,    wherein each aryl or cycloalkyl is unsubstituted or substituted with    halo, C₁₋₄alkyl, or halo-C₁₋₄alkyl;-   A is a 5-membered heteroaryl ring;-   Y is absent or is C₁₋₄alkylene; and-   when Y is absent or is C₁₋₄alkylene, R³ and R⁴ taken together with    the nitrogen to which they are attached form a monocyclic or    bicyclic heterocycloalkyl, unsubstituted or substituted with one or    more R^(g) substituents;    -   wherein each R^(g) substituent is independently C₁₋₄alkyl        (unsubstituted or substituted with one or more C₁₋₄alkoxy,        halo-C₁₋₄alkoxy, or halo groups), C₃₋₇cycloalkyl, C₁₋₄alkoxy,        halo-C₁₋₄alkoxy, or halo;-   or, when Y is C₁₋₄alkylene, R³ and Y taken together with the    nitrogen to which R³ is attached form a monocyclic or bicyclic    heterocycloalkyl ring, which ring is unsubstituted or substituted    with C₁₋₄alkyl or halo; and R⁴ is H or C₁₋₄alkyl; and-   R⁵ is H or C₁₋₄alkyl;-   or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) or (IA) is acompound selected from those species described or exemplified in thedetailed description below.

In a further aspect, the invention relates to a pharmaceuticalcomposition comprising at least one compound of Formula (I) or (IA) or apharmaceutically acceptable salt thereof. Pharmaceutical compositionsaccording to the invention may further comprise a pharmaceuticallyacceptable excipient. The invention is also a compound of Formula (I) or(IA) or a pharmaceutically acceptable salt thereof for use as amedicament.

In another aspect, the invention is directed to a method of treating aneurodegenerative disease or condition associated with protein orpeptide aggregation, comprising administering to a subject in need ofsuch treatment an effective amount of at least one compound of Formula(I) or (IA) or a pharmaceutically acceptable salt thereof. In anotheraspect, described herein is a compound or composition for use intreating a neurodegenerative disease or medical condition associatedwith protein or peptide aggregation.

In another aspect, the invention is directed to a method of treating adisease or medical condition associated with protein or peptideaggregation, comprising administering to a subject in need of suchtreatment an effective amount of at least one compound of Formula (I) or(IA) or a pharmaceutically acceptable salt thereof. The invention isalso directed to the use of a compound of Formula (I) or (IA) or apharmaceutically acceptable salt thereof for the treatment of, or forthe preparation of a medicament for the treatment of, such diseases andmedical conditions.

In yet another aspect, the invention relates to a method of interferingwith the accumulation of protein or peptide aggregates in a cell, ormodulating, preventing, slowing, reversing, or inhibiting protein orpeptide aggregation in a cell, comprising contacting the cell with aneffective amount of at least one compound of Formula (I) or (IA) or asalt thereof, and/or with at least one pharmaceutical composition of theinvention, wherein the contacting is in vitro, ex vivo, or in vivo.

Additional embodiments, features, and advantages of the invention willbe apparent from the following detailed description and through practiceof the invention.

For the sake of brevity, the disclosures of the publications cited inthis specification, including patents, are herein incorporated byreference.

DETAILED DESCRIPTION OF THE INVENTION

Before the present invention is further described, it is to beunderstood that this invention is not limited to particular embodimentsdescribed, as such may, of course, vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the present invention will be limited only by the appendedclaims.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art to which this invention belongs. All patents, applications,published applications and other publications referred to herein areincorporated by reference in their entireties. If a definition set forthin this section is contrary to or otherwise inconsistent with adefinition set forth in a patent, application, or other publication thatis herein incorporated by reference, the definition set forth in thissection prevails over the definition incorporated herein by reference.

As used herein and in the appended claims, the singular forms “a,” “an,”and “the” include plural referents unless the context clearly dictatesotherwise. It is further noted that the claims may be drafted to excludeany optional element. As such, this statement is intended to serve asantecedent basis for use of such exclusive terminology as “solely,”“only” and the like in connection with the recitation of claim elements,or use of a “negative” limitation.

As used herein, the terms “including,” “containing,” and “comprising”are used in their open, non-limiting sense.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum amount of the sameentity that could be obtained under the particular stoichiometricconditions. Concentrations that are given as percentages refer to massratios, unless indicated differently.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, the preferredmethods and materials are now described. All publications mentionedherein are incorporated herein by reference to disclose and describe themethods and/or materials in connection with which the publications arecited.

Except as otherwise noted, the methods and techniques of the presentembodiments are generally performed according to conventional methodswell known in the art and as described in various general and morespecific references that are cited and discussed throughout the presentspecification. See, e.g., Loudon, Organic Chemistry, Fourth Edition, NewYork: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith andMarch, March's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, Fifth Edition, Wiley-Interscience, 2001.

The nomenclature used herein to name the subject compounds isillustrated in the Examples herein. This nomenclature has generally beenderived using the commercially-available ChemBioDraw Ultra software,Version 14.0.0.117.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination. All combinations of the embodimentspertaining to the chemical groups represented by the variables arespecifically embraced by the present invention and are disclosed hereinjust as if each and every combination was individually and explicitlydisclosed, to the extent that such combinations embrace compounds thatare stable compounds (i.e., compounds that can be isolated,characterized, and tested for biological activity). In addition, allsubcombinations of the chemical groups listed in the embodimentsdescribing such variables are also specifically embraced by the presentinvention and are disclosed herein just as if each and every suchsub-combination of chemical groups was individually and explicitlydisclosed herein.

REPRESENTATIVE EMBODIMENTS

In some embodiments of Formula (I) or (IA), all variables are as definedherein (including any of the particular definitions listed below), andone or more of the following limitations also applies:

-   (a1) m is 1 or 2; or-   (a2) m is 1 or 2, and R¹ is as defined herein, wherein at least one    R¹ is C₁₋₄alkyl (substituted with one or two halo groups, or with    —OC₁₋₄alkyl), C₁₋₄alkyl (substituted with —CF₃), —OH, or    —OC₁₋₄alkyl;-   (b) R² is C₁₋₅alkyl substituted with two halo groups, —OC₁₋₄alkyl,    or —SC₁₋₄alkyl, or is monocyclic cycloalkyl substituted with halo,    C₁₋₄alkyl, or halo-C₁₋₄alkyl, or is —C₁₋₄alkyl-(monocyclic    cycloalkyl), wherein the cycloalkyl is unsubstituted or substituted    with halo, C₁₋₄alkyl, or halo-C₁₋₄alkyl, or is aryl substituted with    halo, C₁₋₄alkyl, or halo-C₁₋₄alkyl;-   (c) when R³ and R⁴ taken together with the nitrogen to which they    are attached form a monocyclic heterocycloalkyl, said    heterocycloalkyl is substituted with one or more R^(g) substituents    and R^(g) is as defined herein; and at least one R^(g) substituent    is C₁₋₄alkyl (substituted with one or more C₁₋₄alkoxy,    halo-C₁₋₄alkoxy, or halo groups), C₁₋₄alkoxy, halo-C₁₋₄alkoxy, or    halo.

In some embodiments of the formulae described herein, B is an optionallysubstituted 9-membered bicyclic heteroaryl. In other embodiments, B isoptionally substituted indole, benzofuran, benzothiophene, indazole,benzimidazole, benzoxazole, benzisoxazole, imidazopyridine, orpyrrolopyridine. In other embodiments, B is benzothiophene,benzimidazole, benzisoxazole, imidazopyridine, or pyrrolopyridine (inwhich the pyridine nitrogen is not attached to the same carbon as thepyrrole nitrogen). In other embodiments, B is optionally substitutedindole, benzofuran, benzothiophene, indazole, benzisoxazole,imidazopyridine, or pyrrolopyridine. In other embodiments, B isoptionally substituted indole. In other embodiments, B is optionallysubstituted 3-indole. In other embodiments, B is substituted indole orsubstituted 3-indole. In other embodiments, B is an optionallysubstituted 10-membered bicyclic heteroaryl. In other embodiments, B isoptionally substituted quinoline or isoquinoline. In other embodiments,B is an optionally substituted monocyclic 5- or 6-memberedheterocycloalkyl. In other embodiments, B is optionally substitutedpyrrolidine, piperidine, piperazine, or morpholine.

In some embodiments, m is 0. In other embodiments, m is 1. In otherembodiments, m is 2.

In some embodiments, each R¹ substituent is independently —OH, or isfluoro, chloro, bromo, or iodo. In other embodiments, each R¹ is fluoroor bromo. In other embodiments, each R¹ substituent is independentlymethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl,tert-butyl, or is C₁₋₄alkyl (substituted with one or more fluoro,chloro, bromo, methoxy, ethoxy, propoxy, isopropoxy, or butoxy groups).In other embodiments, each R¹ is independently halo or C₁₋₄alkyloptionally substituted with one or more halo groups. In otherembodiments, each R¹ is independently OMe, OCHF₂, OCF₃, OEt, OiPr, Me,CF₃, Cl, or CH₂F, CHF₂.

In some embodiments, R² is H. In other embodiments, R² is C₁₋₅alkyl(unsubstituted or substituted with one or more halo substituents). Inother embodiments, R² is —OC₁₋₄alkyl or —SC₁₋₄alkyl. In otherembodiments, R² is C₁₋₅alkyl (substituted with one or more halosubstituents). In other embodiments, R² is unsubstituted C₁₋₅alkyl or isC₁₋₅alkyl substituted as described herein. In other embodiments, R² isunsubstituted C₃₋₅alkyl or is C₃₋₅alkyl substituted as described herein.In other embodiments, R² is methyl, ethyl, propyl, butyl, or isopentyl.In other embodiments, R² is 1,1-difluorobutyl, trifluoro-isopentyl,trifluorobutyl, 3,3-difluorobutyl, 2,2-difluorobutyl, or propoxy. Inother embodiments, R² is monocyclic cycloalkyl or —C₁₋₄alkyl-(monocycliccycloalkyl), wherein each cycloalkyl is unsubstituted or substitutedwith halo, C₁₋₄alkyl, or halo-C₁₋₄alkyl. In some embodiments, R² iscyclobutyl, cyclopentyl, cyclopentadienyl, cyclohexyl, or cycloheptyl,each optionally substituted with one or two substituents selected fromthe group consisting of methyl, halo, or trifluoromethyl. In someembodiments, R² is substituted monocyclic cycloalkyl or substituted—C₁₋₄alkyl-(monocyclic cycloalkyl). In some embodiments, R² iscyclopropylethyl, (3-methylcyclobutyl)methyl, or(3,3-difluorocyclobutyl)methyl. In other embodiments, R² iscyclobutylmethyl. In some embodiments, R² is substituted C₁₋₅alkyl,substituted monocyclic cycloalkyl, or substituted —C₁₋₄alkyl-(monocycliccycloalkyl). In other embodiments, R² is optionally substituted aryl. Inother embodiments, R² is optionally substituted phenyl. In otherembodiments, R² is phenyl. In other embodiments, R² is substituted arylor substituted phenyl. In some embodiments, R² is methyl, ethyl, propyl,or isobutyl.

In some embodiments, the carbon to which R² is attached is in the Rconfiguration. In other embodiments, the carbon to which R² is attachedis in the S configuration.

In some embodiments, A is pyrrole, furan, thiophene, pyrazole,imidazole, oxazole, isoxazole, thiazole, triazole, oxadiazole,thiadiazole, or tetrazole. In other embodiments, A is pyrrole, furan,thiophene, pyrazole, imidazole, oxazole, thiazole, triazole, oxadiazole,thiadiazole, or tetrazole. In other embodiments, A is imidazole,oxazole, or thiazole. In other embodiments, A is thiazole.

In some embodiments, Y is absent. In other embodiments, Y is —CH₂—,—CH₂CH₂—, —CH(CH₃)—, —(CH₂)₃—, —C(CH₃)₂—, —(CH₂)₄—, —CH((CH₂)₂CH₃)—,—CH(CH(CH₃)₂)—, —CH(CH₂CH₃)CH₂—, —CH(CH₃)CH(CH₃)—, —CH(CH₃)(CH₂)₂—, or—CH₂CH(CH₃)CH₂—. In other embodiments, Y is —CH₂—, —CH₂CH₂—, or—CH(CH₃)—. In still other embodiments, Y is —CH₂CH₂—.

In some embodiments, where Y is absent or is C₁₋₄alkylene, R³ and R⁴taken together with the nitrogen to which they are attached form amonocyclic or bicyclic heterocycloalkyl ring, unsubstituted orsubstituted with one or more R^(g) substituents. In other embodiments,R³ and R⁴ taken together with the nitrogen to which they are attachedform azetidine, pyrrolidine, piperidine, piperazine, morpholine,thiomorpholine, 1,1-dioxo-thiomorpholine, azepine, or diazepine, eachunsubstituted or substituted with one or more R^(g) substituents. Inother embodiments, R³ and R⁴ taken together with the nitrogen to whichthey are attached form piperidine, piperazine, or diazepine, eachunsubstituted or substituted with one or more R^(g) substituents. Inother embodiments, R³ and R⁴ taken together with the nitrogen to whichthey are attached form piperazine substituted with one, two, or threeR^(g) substituents. In other embodiments, R³ and R⁴ taken together withthe nitrogen to which they are attached form piperazine, unsubstitutedor substituted with C₁₋₄alkyl. In still other embodiments, R³ and R⁴taken together with the nitrogen to which they are attached formpiperazine or 4-methylpiperazine. In some embodiments in which R³ and R⁴taken together with the nitrogen to which they are attached form amonocyclic heterocycloalkyl ring, unsubstituted or substituted with oneor more R^(g) substituents, Y is absent, or Y is C₂₋₄alkylene.

In some embodiments, each R^(g) substituent is independently methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or iscyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or is methoxy,ethoxy, propoxy, or isopropoxy, or is trifluoromethoxy ortrifluoroethoxy, or is bromo, chloro, or fluoro, each unsubstituted orsubstituted as described herein. In other embodiments, each R^(g)substituent is independently ethyl, isopropyl, cyclopropyl, tert-butyl,isobutyl, 2-methoxyethyl, 2,2-difluoroethyl, trifluoroethyl,trifluoroethoxy-ethyl, trifluoromethyl, difluoromethyl, or fluoromethyl,or is fluoroethyl, methoxyethyl, trifluoromethoxyethyl, ortrifluoromethyl.

In some embodiments, there are 0, 1, 2, or 3 R^(g) substituents. Inother embodiments, there is one, or there are two, or there are threeR^(g) substituents.

In some embodiments, where Y is C₁₋₄alkylene, R³ and Y are takentogether with the nitrogen to which R³ is attached form a monocyclicheterocycloalkyl ring, which ring is unsubstituted or substituted withC₁₋₄alkyl or halo; and R⁴ is H or C₁₋₄alkyl. In other embodiments, Y andR³ taken together with the nitrogen to which R³ is attached formpyrrolidine or piperidine, which ring is optionally substituted asdescribed herein. In other embodiments, R⁴ is H or methyl.

In some embodiments of Formula (I) or (IA), R³ and R⁴ taken togetherwith the nitrogen to which they are attached form a monocyclicheterocycloalkyl ring, substituted with one or more R^(g) substituents;wherein R^(g) is as defined herein; and at least one R^(g) substituentis C₁₋₄alkyl (substituted with one or more C₁₋₄alkoxy, halo-C₁₋₄alkoxy,or halo groups), C₁₋₄alkoxy, halo-C₁₋₄alkoxy, or halo. In someembodiments, R³ and R⁴ taken together with the nitrogen to which theyare attached form

optionally substituted with methyl, for example, as

In some embodiments, R² is C₁₋₅alkyl (substituted with one or more halosubstituents), —OC₁₋₄alkyl, or —SC₁₋₄alkyl, or a monocyclic cycloalkylor —C₁₋₄alkyl-(monocyclic cycloalkyl), wherein each cycloalkyl issubstituted with halo, C₁₋₄alkyl, or halo-C₁₋₄alkyl.

In some embodiments, R⁵ is H. In other embodiments, R⁵ is C₁₋₄alkyl. Inother embodiments, R⁵ is H or methyl.

In some embodiments, the compound of Formula (I) or (IA) is a compoundof Formula (II):

whereinB′ is a 5-membered heteroaryl;B″ is phenyl or a 6-membered heteroaryl; andR¹, R², R³, R⁴, R⁵, m, A, and Y are as defined herein;or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) or (IA) is a compoundof Formula (III):

whereinB′ is a 5-membered heteroaryl;B″ is phenyl or a 6-membered heteroaryl; andR¹, R², R³, R⁴, R⁵, m, and Y are as defined herein;or a pharmaceutically acceptable salt thereof.

In some embodiments of the formulae described herein, B′ and B″ togetherform indole, benzofuran, benzothiophene, indazole, benzimidazole,benzoxazole, benzisoxazole, imidazopyridine, or pyrrolopyridine. Inother embodiments, B′ and B″ together are optionally substituted indole,benzofuran, benzothiophene, indazole, benzisoxazole, imidazopyridine, orpyrrolopyridine. In other embodiments, B′ and B″ together are optionallysubstituted indole. In other embodiments, B′ and B″ together areoptionally substituted 3-indole. In some embodiments, B′ and B″ togetherare substituted indole or substituted 3-indole. In some embodiments, mis 0. In other embodiments, m is 1. In other embodiments, m is 2.

In other embodiments, the compound of Formula (I) or (IA) is not acompound in Table X:

TABLE X Structure Chemical Name

N-(1-(1H-Indol-3-yl)- hexan-2-yl)-2-(4- methylpiperazin-1-yl)-thiazole-5-carboxamide

N-(2-(1H-Indol-3-yl)- ethyl)-2-(4-methyl- piperazin-1-yl)thiazole-5-carboxamide

N-(1-(1H-Indol-3-yl)- hexan-2-yl)-2- (piperazin-1-yl)thiazole-5-carboxamide

N-(2-(1H-Indol-3-yl)- ethyl)-2-(2-(4- methylpiperazin-1-yl)ethyl)thiazole-5- carboxamide

N-(1-(1H-Indol-3-yl)- hexan-2-yl)-2-(2-(4- methylpiperazin-1-yl)ethyl)thiazole-5- carboxamide

N-(1-(1H-Indol-3-yl)- hexan-2-yl)-2-(4- methylpiperazin- 1-yl)oxazole-5-carboxamide

N-(1-(1H-Indol-3-yl)- hexan-2-yl)-5-(4- methylpiperazin-1-yl)-1,3,4-thiadiazole-2- carboxamide

N-(1-(1H-Indol-3-yl)- hexan-2-yl)-5-(4- methylpiperazin-1-yl)-4H-1,2,4-triazole- 3-carboxamide

N-(1-(1H-Indol-3-yl)- hexan-2-yl)-2-(4- methylpiperazin-1-yl)-1H-imidazole-5- carboxamide

N-(1-(5-Fluoro-1H- indol-3-yl)hexan-2-yl)- 2-(2-morpholinoethyl)-thiazole-5-carboxamide

N-(1-(1H-Indol-3-yl)- hexan-2-yl)-2- morpholinothiazole- 5-carboxamide

N-(1-(1H-indol-3-yl)- hexan-2-yl)-2- (pyrrolidin-1-yl)thiazole-5-carboxamide

N-(1-(1H-indol-3-yl)- hexan-2-yl)-2-(2- morpholinoethyl)-thiazole-5-carboxamide

N-(1-(5-fluoro-1H- indol-3-yl)hexan-2- yl)-2-(4-methyl-piperazin-1-yl)thiazole- 5-carboxamide

N-(1-(1H-indol-3- yl)hexan-2-yl)-N- methyl-2-(4-methyl-piperazin-1-yl)thiazole- 5-carboxamide

N-(1-(6-fluoro-1H- indol-3-yl)hexan- 2-yl)-2-(4-methyl-piperazin-1-yl)thiazole- 5-carboxamide

N-(1-(5,6-difluoro- 1H-indol-3-yl)hexan- 2-yl)-2-(4-methyl-piperazin-1-yl)thiazole- 5-carboxamide

2-(4-methylpiperazin- 1-yl)-N-(6,6,6-trifluoro- 1-(1H-indol-3-yl)-hexan-2-yl)thiazole- 5-carboxamide

N-(1-(1H-indol-3-yl)- hexan-2-yl)-5- morpholino-1,3,4- thiadiazole-2-carboxamide

N-(1-(1H-indol-3- yl)hexan-2-yl)-5-(2- (4-methylpiperazin-1-yl)ethyl)-1,3,4- thiadiazole-2- carboxamide

N-(1-(5-fluoro-1H- indol-3-yl)hexan-2- yl)-5-(2-(4-methyl-piperazin-1-yl)ethyl)- 1,3,4-thiadiazole-2- carboxamide

N-(1-(1H-indol-3- yl)hexan-2-yl)-2- (1-methylpiperidin- 4-yl)thiazole-5-carboxamide

N-(1-(1H-indol-3- yl)hexan-2-yl)-5- (pyrrolidin-1-yl)-1,3,4-thiadiazole-2- carboxamide

N-(1-(1H-indol-3- yl)hexan-2-yl)-N- methyl-5-(4- methylpiperazin-1-yl)-1,3,4-thiadiazole- 2-carboxamide

N-(1-(1H-indol-3- yl)hexan-2-yl)-5-(1- methylpiperidin-4-yl)-1,3,4-thiadiazole- 2-carboxamide

N-(1-(1H-indol-3- yl)hexan-2-yl)-2-(4- methyl-1,4-diazepan-1-yl)thiazole-5- carboxamideor a pharmaceutically acceptable salt thereof.

In other embodiments, the compound of Formula (I) or (IA) is selectedfrom the group consisting of:

Ex. Structure Chemical Name 1

N-(1-(1H-indol-3- yl)hexan-2-yl)-2- (4-ethylpiperazin- 1-yl)thiazole-5-carboxamide 2

N-(1-(1H-indol-3- yl)hexan-2-yl)-2-(4- isopropylpiperazin-1-yl)thiazole-5- carboxamide 3

N-(1-(1H-indol-3- yl)hexan-2-yl)-2- (4-cyclopropyl- piperazin-1-yl)-thiazole-5- carboxamide 4

N-(1-(1H-indol-3- yl)hexan-2-yl)-2- (4-(tert-butyl)- piperazin-1-yl)-thiazole-5- carboxamide 5

N-(1-(1H-indol-3- yl)hexan-2-yl)- 2-(4-isobutyl- piperazin-1-yl)-thiazole-5- carboxamide 6

N-(1-(1H-indol-3- yl)hexan-2-yl)- 2-(4-(2-methoxy- ethyl)piperazin-1-yl)thiazole-5- carboxamide 7

N-(1-(1H-indol-3- yl)hexan-2-yl)-2- (4-(2-fluoroethyl)- piperazin-1-yl)-thiazole-5- carboxamide 8

N-(1-(1H-indol-3- yl)hexan-2-yl)-2- (4-(2,2-difluoro- ethyl)piperazin-1-yl)thiazole-5- carboxamide 9

N-(1-(1H-indol-3- yl)hexan-2-yl)-2- (4-(2,2,2-trifluoro-ethyl)piperazin- 1-yl)thiazole-5- carboxamide 10

N-(1-(1H-indol-3- yl)hexan-2-yl)-2- (4-(3,3,3-trifluoro-propyl)piperazin- 1-yl)thiazole-5- carboxamide 11

N-(1-(1H-indol-3- yl)hexan-2-yl)-2- (3,4-dimethyl- piperazin-1-yl)-thiazole-5- carboxamide 12

N-(1-(1H-indol-3- yl)hexan-2-yl)-2- (3,3,4-trimethyl- piperazin-1-yl)-thiazole-5- carboxamide 13

N-(1-(1H-indol- 3-yl)hexan-2-yl)- 2-(cis-3,4,5- trimethylpiperazin-1-yl)thiazole-5- carboxamide 14

N-(1-(1H-indol- 3-yl)-5-methyl- hexan-2-yl)-2-(4- methylpiperazin-1-yl)thiazole-5- carboxamide 15

N-(1-cyclopentyl- 2-(1H-indol-3- yl)ethyl)-2-(4- methylpiperazin-1-yl)thiazole-5- carboxamide 16

N-(2-(1H-indol-3- yl)ethyl)-N-butyl- 2-(4-methyl- piperazin-1-yl)-thiazole-5- carboxamide 17

N-(1-(1H-indol-3- yl)hexan-2-yl)-2- (3-(difluoromethyl)-4-methylpiperazin- 1-yl)thiazole-5- carboxamide 18

N-(1-(1H-indol-3- yl)hexan-2-yl)-2- (3-(fluoromethyl)-4-methylpiperazin- 1-yl)thiazole-5- carboxamide 19

N-(1-(1H-indol-3- yl)hexan-2-yl)-2- (8-methyl-3,8- diazabicyclo[3.2.1]-octan-3-yl)thiazole- 5-carboxamide 20

N-(2-(1H-indol-3- yl)-1-phenylethyl)- 2-(4-methyl- piperazin-1-yl)-thiazole-5- carboxamide 21

N-(2-(1H-indol-3- yl)ethyl)-N- methyl-2-(4- methylpiperazin-1-yl)thiazole-5- carboxamideand pharmaceutically acceptable salts thereof.

In other embodiments, the compound of Formula (I) or (IA) is selectedfrom the group consisting of:

Ex. Compound 22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

and pharmaceutically acceptable salts thereof.

In some embodiments, the compound of Formula (I) or (IA) is selectedfrom the group consisting of Examples 1-62, and pharmaceuticallyacceptable salts thereof.

In still other embodiments, the compound of Formula (I) or (IA) isselected from the group consisting of:

Ex. Compound 63

64

65

66

67

68

69

70

and pharmaceutically acceptable salts thereof.

In other embodiments, the compound of Formula (I) or (IA) is selectedfrom the group consisting of Examples 1-70, and pharmaceuticallyacceptable salts thereof.

In further embodiments, the compound is selected from the compounds inList 1 below, and pharmaceutically acceptable salts thereof.

Chemical Definitions

The term “alkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain. “C_(x-y)alkyl” refers toalkyl groups with x to y carbon atoms. For example, “C₁₋₄alkyl” refersto alkyl groups with 1 to 4 carbon atoms in the chain. Examples of alkylgroups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl,hexyl, and isohexyl.

The term “alkoxy” refers to an alkyl-O— group, where alkyl is as definedabove. The alkoxy group is connected to the parent structure via theoxygen atom. “C₁₋₄alkoxy” refers to alkoxy groups in which an alkylgroup with 1 to 4 carbon atoms is bonded to the oxygen.

The term “alkylene” refers to a divalent group that is a radical of analkane. The alkylene can be a straight- or branched-chain divalent alkylradical. “C₁₋₄ alkylene” refers to alkylene groups with 1 to 4 carbonatoms.

The term “aryl” refers to a monovalent aromatic carbocyclic group offrom 6 to 14 carbon atoms having a single ring (a phenyl group) or amultiple condensed ring (such as napthyl, anthracenyl, or indanyl), inwhich condensed rings are optionally aromatic, provided that the pointof attachment of the aryl group to the parent structure is through anatom of an aromatic ring.

The term “cycloalkyl” refers to a saturated or partially saturated,monocyclic, fused polycyclic, bridged polycyclic, or spiro polycycliccarbocycle having from 3 to 12 ring atoms per carbocycle. Illustrativeexamples of cycloalkyl groups include the following entities, in theform of properly bonded moieties:

The term “halogen” represents chlorine, fluorine, bromine, or iodine.The term “halo” represents chloro, fluoro, bromo, or iodo.

The term “halo-alkyl” refers to an alkyl group as described herein,wherein one or more hydrogen atoms on the alkyl group have beensubstituted with a halo group. Examples of such groups include, withoutlimitation, fluoroalkyl groups, such as fluoromethyl, difluoromethyl,trifluoromethyl, fluoroethyl, trifluoroethyl, and the like.

The term “haloalkoxy” refers to the group alkyl-O— wherein one or morehydrogen atoms on the alkyl group have been replaced with a halo groupand include, by way of examples, groups such as trifluoromethoxy,fluoroethoxy, and the like.

The term “heteroalkylene” refers to a divalent alkylene group in whichone carbon chain atom is replaced by —S—, —O—, or —NR—, where R is H orC₁₋₄alkyl.

The term “heteroaryl” refers to a monocyclic, fused bicyclic, or fusedpolycyclic aromatic heterocycle (ring structure having ring atomsselected from carbon atoms and up to four heteroatoms selected fromnitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms. Bicyclicheteroaryl groups include bicyclic groups with one aromatic and onenonaromatic ring.

Where a heteroaryl ring is substituted with —OH, one of ordinary skillwould understand that the resulting ring system may be drawn as thecorresponding oxo-substituted tautomer. Illustrative examples ofheteroaryl groups include the following entities, in the form ofproperly bonded moieties:

The term “heterocycloalkyl” refers to a saturated or partiallyunsaturated group having a single ring or multiple condensed rings,including fused, bridged, or spiro ring systems, and having from 3 to 20ring atoms, including 1 to 10 heteroatoms. These ring atoms are selectedfrom the group consisting of carbon, nitrogen, sulfur, or oxygen. Incertain embodiments, the nitrogen and/or sulfur atom(s) of theheterocyclic group are optionally oxidized to provide for N-oxide,—S(O)—, or —SO₂— moieties. Illustrative examples of heterocyclic groupsinclude the following entities, in the form of properly bonded moieties:

The term “oxo” represents a carbonyl oxygen. For example, a cyclopentylsubstituted with oxo is cyclopentanone.

Those skilled in the art will recognize that the species listed orillustrated in the definitions provided herein are not exhaustive, andthat additional species within the scope of these defined terms may alsobe selected.

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents. Where the term “substituted” is used to describe astructural system, the substitution is meant to occur at anyvalency-allowed position on the system.

Any formula depicted herein is intended to represent a compound of thatstructural formula as well as certain variations or forms. For example,a formula given herein is intended to include a racemic form, or one ormore enantiomeric, diastereomeric, or geometric isomers, or a mixturethereof. Additionally, any formula given herein is intended to referalso to a hydrate, solvate, or polymorph of such a compound, or amixture thereof.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S,¹⁸F, ³⁶Cl, and ¹²⁵I, respectively. Such isotopically labelled compoundsare useful in metabolic studies (preferably with ¹⁴C), reaction kineticstudies (with, for example ²H or ³H), detection or imaging techniques[such as positron emission tomography (PET) or single-photon emissioncomputed tomography (SPECT)] including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or ¹¹C labeled compound may be particularly preferredfor PET or SPECT studies. PET and SPECT studies may be performed asdescribed, for example, by Brooks, D. J., “Positron Emission Tomographyand Single-Photon Emission Computed Tomography in Central Nervous SystemDrug Development,” NeuroRx 2005, 2(2), 226-236, and references citedtherein. Further, substitution with heavier isotopes such as deuterium(i.e., ²H) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements. Isotopically labeled compounds of thisinvention and prodrugs thereof can generally be prepared by carrying outthe procedures disclosed in the schemes or in the examples andpreparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent.

The nomenclature “C_(i-j)” with j>i, when applied herein to a class ofsubstituents, is meant to refer to embodiments of this invention forwhich each and every one of the number of carbon members, from i to jincluding i and j, is independently realized. By way of example, theterm C₁₋₃ refers independently to embodiments that have one carbonmember (C₁), embodiments that have two carbon members (C₂), andembodiments that have three carbon members (C₃).

Any disubstituent referred to herein is meant to encompass the variousattachment possibilities when more than one of such possibilities areallowed. For example, reference to disubstituent -A-B—, where A≠B,refers herein to such disubstituent with A attached to a firstsubstituted member and B attached to a second substituted member, and italso refers to such disubstituent with A attached to the secondsubstituted member and B attached to the first substituted member.

The invention also includes pharmaceutically acceptable salts of thecompounds represented by Formula (I) or (IA), preferably of thosedescribed above and of the specific compounds exemplified herein, andpharmaceutical compositions comprising such salts, and methods of usingsuch salts.

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of a compound represented herein that is non-toxic,biologically tolerable, or otherwise biologically suitable foradministration to the subject. See, generally, S. M. Berge, et al.,“Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19. Preferredpharmaceutically acceptable salts are those that are pharmacologicallyeffective and suitable for contact with the tissues of subjects withoutundue toxicity, irritation, or allergic response. A compound describedherein may possess a sufficiently acidic group, a sufficiently basicgroup, both types of functional groups, or more than one of each type,and accordingly react with a number of inorganic or organic bases, andinorganic and organic acids, to form a pharmaceutically acceptable salt.

Examples of pharmaceutically acceptable salts include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogen-phosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,methylsulfonates, propylsulfonates, besylates, xylenesulfonates,naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates,phenylpropionates, phenylbutyrates, citrates, lactates,γ-hydroxybutyrates, glycolates, tartrates, and mandelates. Lists ofother suitable pharmaceutically acceptable salts are found inRemington's Pharmaceutical Sciences, 17th Edition, Mack PublishingCompany, Easton, Pa., 1985.

For a compound of Formula (I) or (IA) that contains a basic nitrogen, apharmaceutically acceptable salt may be prepared by any suitable methodavailable in the art, for example, treatment of the free base with aninorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuricacid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and thelike, or with an organic acid, such as acetic acid, phenylacetic acid,propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid,hydroxymaleic acid, isethionic acid, succinic acid, valeric acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidylacid, such as glucuronic acid or galacturonic acid, an alpha-hydroxyacid, such as mandelic acid, citric acid, or tartaric acid, an aminoacid, such as aspartic acid or glutamic acid, an aromatic acid, such asbenzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, asulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid,methanesulfonic acid, or ethanesulfonic acid, or any compatible mixtureof acids such as those given as examples herein, and any other acid andmixture thereof that are regarded as equivalents or acceptablesubstitutes in light of the ordinary level of skill in this technology.

The invention also relates to pharmaceutically acceptable prodrugs ofthe compounds of Formula (I) or (IA), and treatment methods employingsuch pharmaceutically acceptable prodrugs. The term “prodrug” means aprecursor of a designated compound that, following administration to asubject, yields the compound in vivo via a chemical or physiologicalprocess such as solvolysis or enzymatic cleavage, or under physiologicalconditions (e.g., a prodrug on being brought to physiological pH isconverted to the compound of Formula (I) or (IA)). A “pharmaceuticallyacceptable prodrug” is a prodrug that is non-toxic, biologicallytolerable, and otherwise biologically suitable for administration to thesubject. Illustrative procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in “Design ofProdrugs”, ed. H. Bundgaard, Elsevier, 1985.

The present invention also relates to pharmaceutically activemetabolites of compounds of Formula (I) or (IA), and uses of suchmetabolites in the methods of the invention. A “pharmaceutically activemetabolite” means a pharmacologically active product of metabolism inthe body of a compound of Formula (I) or (IA) or salt thereof. Prodrugsand active metabolites of a compound may be determined using routinetechniques known or available in the art. See, e.g., Bertolini et al.,J. Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86(7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv.Drug Res. 1984, 13, 255-331; Bundgaard, Design of Prodrugs (ElsevierPress, 1985); and Larsen, Design and Application of Prodrugs, DrugDesign and Development (Krogsgaard-Larsen et al., eds., Harwood AcademicPublishers, 1991).

Pharmaceutical Compositions

For treatment purposes, pharmaceutical compositions comprising thecompounds described herein may further comprise one or morepharmaceutically-acceptable excipients. A pharmaceutically-acceptableexcipient is a substance that is non-toxic and otherwise biologicallysuitable for administration to a subject. Such excipients facilitateadministration of the compounds described herein and are compatible withthe active ingredient. Examples of pharmaceutically-acceptableexcipients include stabilizers, lubricants, surfactants, diluents,anti-oxidants, binders, coloring agents, bulking agents, emulsifiers, ortaste-modifying agents. In preferred embodiments, pharmaceuticalcompositions according to the invention are sterile compositions.Pharmaceutical compositions may be prepared using compounding techniquesknown or that become available to those skilled in the art.

Sterile compositions are also contemplated by the invention, includingcompositions that are in accord with national and local regulationsgoverning such compositions.

The pharmaceutical compositions and compounds described herein may beformulated as solutions, emulsions, suspensions, or dispersions insuitable pharmaceutical solvents or carriers, or as pills, tablets,lozenges, suppositories, sachets, dragees, granules, powders, powdersfor reconstitution, or capsules along with solid carriers according toconventional methods known in the art for preparation of various dosageforms. Pharmaceutical compositions of the invention may be administeredby a suitable route of delivery, such as oral, parenteral, rectal,nasal, topical, or ocular routes, or by inhalation. Preferably, thecompositions are formulated for intravenous or oral administration.

For oral administration, the compounds the invention may be provided ina solid form, such as a tablet or capsule, or as a solution, emulsion,or suspension. To prepare the oral compositions, the compounds of theinvention may be formulated to yield a dosage of, e.g., from about 0.01to about 50 mg/kg daily, or from about 0.05 to about 20 mg/kg daily, orfrom about 0.1 to about 10 mg/kg daily. Additional dosages include fromabout 0.1 mg to 1 g daily, from about 1 mg to about 10 mg daily, fromabout 10 mg to about 50 mg daily, from about 50 mg to about 250 mgdaily, or from about 250 mg to 1 g daily. Oral tablets may include theactive ingredient(s) mixed with compatible pharmaceutically acceptableexcipients such as diluents, disintegrating agents, binding agents,lubricating agents, sweetening agents, flavoring agents, coloring agentsand preservative agents. Suitable inert fillers include sodium andcalcium carbonate, sodium and calcium phosphate, lactose, starch, sugar,glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, andthe like. Exemplary liquid oral excipients include ethanol, glycerol,water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starchglycolate, microcrystalline cellulose, and alginic acid are exemplarydisintegrating agents. Binding agents may include starch and gelatin.The lubricating agent, if present, may be magnesium stearate, stearicacid, or talc. If desired, the tablets may be coated with a materialsuch as glyceryl monostearate or glyceryl distearate to delay absorptionin the gastrointestinal tract, or may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, active ingredient(s) may be mixed witha solid, semi-solid, or liquid diluent. Soft gelatin capsules may beprepared by mixing the active ingredient with water, an oil such aspeanut oil or olive oil, liquid paraffin, a mixture of mono anddi-glycerides of short chain fatty acids, polyethylene glycol 400, orpropylene glycol.

Liquids for oral administration may be in the form of suspensions,solutions, emulsions, or syrups, or may be lyophilized or presented as adry product for reconstitution with water or other suitable vehiclebefore use. Such liquid compositions may optionally contain:pharmaceutically-acceptable excipients such as suspending agents (forexample, sorbitol, methyl cellulose, sodium alginate, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel andthe like); non-aqueous vehicles, e.g., oil (for example, almond oil orfractionated coconut oil), propylene glycol, ethyl alcohol, or water;preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbicacid); wetting agents such as lecithin; and, if desired, flavoring orcoloring agents.

The inventive compositions may be formulated for rectal administrationas a suppository. For parenteral use, including intravenous,intramuscular, intraperitoneal, intranasal, or subcutaneous routes, theagents of the invention may be provided in sterile aqueous solutions orsuspensions, buffered to an appropriate pH and isotonicity or inparenterally acceptable oil. Suitable aqueous vehicles include Ringer'ssolution and isotonic sodium chloride. Such forms may be presented inunit-dose form such as ampoules or disposable injection devices, inmulti-dose forms such as vials from which the appropriate dose may bewithdrawn, or in a solid form or pre-concentrate that can be used toprepare an injectable formulation. Illustrative infusion doses rangefrom about 1 to 1000 μg/kg/minute of agent admixed with a pharmaceuticalcarrier over a period ranging from several minutes to several days.

For nasal, inhaled, or oral administration, the inventive pharmaceuticalcompositions may be administered using, for example, a spray formulationalso containing a suitable carrier.

For topical applications, the compounds of the present invention arepreferably formulated as creams or ointments or a similar vehiclesuitable for topical administration. For topical administration, theinventive compounds may be mixed with a pharmaceutical carrier at aconcentration of about 0.1% to about 10% of drug to vehicle. Anothermode of administering the agents of the invention may utilize a patchformulation to effect transdermal delivery.

As used herein, the terms “treat” or “treatment” encompass both“preventative” and “curative” treatment. “Preventative” treatment ismeant to indicate a postponement of development of a disease, a symptomof a disease, or medical condition, suppressing symptoms that mayappear, or reducing the risk of developing or recurrence of a disease orsymptom. “Curative” treatment includes reducing the severity of orsuppressing the worsening of an existing disease, symptom, or condition.Thus, treatment includes ameliorating or preventing the worsening ofexisting disease symptoms, preventing additional symptoms fromoccurring, ameliorating or preventing the underlying systemic causes ofsymptoms, inhibiting the disorder or disease, e.g., arresting thedevelopment of the disorder or disease, relieving the disorder ordisease, causing regression of the disorder or disease, relieving acondition caused by the disease or disorder, or stopping the symptoms ofthe disease or disorder.

The term “subject” refers to a mammalian patient in need of suchtreatment, such as a human.

Exemplary neurodegenerative diseases that are characterized by proteinaggregation include Alzheimer's Disease, Parkinson's Disease,fronto-temporal Dementia, Dementia with Lewy Bodies (Lewy body disease),Parkinson's Disease with Dementia, Multiple System Atrophy, AmyotrophicLateral Sclerosis, and Huntington's Disease, as well as cancers andinflammatory diseases such as Crohn's disease.

In one aspect, the compounds and pharmaceutical compositions of theinvention specifically target α-synuclein, β-amyloid, and/or tau proteinaggregates. Thus, these compounds and pharmaceutical compositions can beused to modulate, prevent, reverse, slow, or inhibit aggregation ofα-synuclein, β-amyloid, and/or tau proteins, and are used in methods ofthe invention to treat degenerative neurological diseases related to orcaused by aggregation, e.g., such as aggregation of α-synuclein,β-amyloid, and/or tau proteins. Preferably, the methods of the inventiontarget neurodegenerative diseases associated with aggregation ofα-synuclein, β-amyloid, and/or tau protein. In preferred embodiments,methods of treatment target Parkinson's disease, Alzheimer's disease,Lewy body disease, or multiple system atrophy. In other embodiments, themethods target cancer or melanoma. The compounds, compositions, andmethod of the present invention are also used to mitigate deleteriouseffects that are secondary to protein aggregation, such as neuronal celldeath.

In some aspects, the compounds, compositions, and methods of theinvention are used to target α-synuclein (SYN) aggregation. Inalternative aspects, the compounds, compositions, and methods of theinvention are used to target Aβ aggregation.

In the inhibitory methods of the invention, an “effective amount” meansan amount sufficient to reduce, slow the progression of, or reverseprotein or peptide aggregation. Measuring the amount of aggregation maybe performed by routine analytical methods such as those describedbelow. Such modulation is useful in a variety of settings, including invitro assays. In such methods, the cell is preferably a nerve cell.

In treatment methods according to the invention, an “effective amount”means an amount or dose sufficient to generally bring about the desiredtherapeutic benefit in subjects needing such treatment. Effectiveamounts or doses of the compounds of the invention may be ascertained byroutine methods, such as modeling, dose escalation, or clinical trials,taking into account routine factors, e.g., the mode or route ofadministration or drug delivery, the pharmacokinetics of the agent, theseverity and course of the infection, the subject's health status,condition, and weight, and the judgment of the treating physician. Anexemplary dose is in the range of about 1 μg to 2 mg of active agent perkilogram of subject's body weight per day, preferably about 0.05 to 100mg/kg/day, or about 1 to 35 mg/kg/day, or about 0.1 to 10 mg/kg/day. Inalternative embodiments an exemplary dose is in the range of about 1 mgto about 1 g per day, or about 1-500, 1-250, 1-100, 1-50, 50-500, or250-500 mg per day. The total dosage may be given in single or divideddosage units (e.g., BID, TID, QID).

Once improvement of the patient's disease has occurred, the dose may beadjusted for preventative or maintenance treatment. For example, thedosage or the frequency of administration, or both, may be reduced as afunction of the symptoms, to a level at which the desired therapeutic orprophylactic effect is maintained. Of course, if symptoms have beenalleviated to an appropriate level, treatment may cease. Patients may,however, require intermittent treatment on a long-term basis upon anyrecurrence of symptoms. Patients may also require chronic treatment on along-term basis.

Drug Combinations

The inventive compounds described herein may be used in pharmaceuticalcompositions or methods in combination with one or more additionalactive ingredients in the treatment of neurodegenerative disorders.Further additional active ingredients for cancer applications includeother cancer therapeutics or agents that mitigate adverse effects ofcancer chemotherapeutic agents. Such combinations may serve to increaseefficacy, ameliorate other disease symptoms, decrease one or more sideeffects, or decrease the required dose of an inventive compound. Theadditional active ingredients may be administered in a separatepharmaceutical composition from a compound of the present invention ormay be included with a compound of the present invention in a singlepharmaceutical composition. The additional active ingredients may beadministered simultaneously with, prior to, or after administration of acompound of the present invention.

Combination agents include additional active ingredients are those thatare known or discovered to be effective in treating neurodegenerativedisorders, including those active against another target associated withthe disease, such as but not limited to, a) compounds that addressprotein misfolding (such as drugs which reduce the production of theseproteins, which increase their clearance or which alter theiraggregation and/or propagation); b) compounds that treat symptoms ofsuch disorders (e.g., dopamine replacement therapies); and c) drugs thatact as neuroprotectants by complementary mechanisms (e.g., thosetargeting autophagy, those that are anti-oxidants, and those acting byother mechanisms such as adenosine A2A antagonists).

For example, compositions and formulations of the invention, as well asmethods of treatment, can further comprise other drugs orpharmaceuticals, e.g., other active agents useful for treating orpalliative for a degenerative neurological disease related to or causedby protein aggregation, e.g., synuclein, beta-amyloid and/or tau proteinaggregation, e.g., Parkinson's disease, Alzheimer's Disease (AD), Lewybody disease (LBD) and multiple system atrophy (MSA), or relatedsymptoms or conditions. For example, the pharmaceutical compositions ofthe invention may additionally comprise one or more of such activeagents, and methods of treatment may additionally comprise administeringan effective amount of one or more of such active agents. In certainembodiments, additional active agents may be antibiotics (e.g.,antibacterial or bacteriostatic peptides or proteins), e.g., thoseeffective against gram positive or negative bacteria, fluids, cytokines,immunoregulatory agents, anti-inflammatory agents, complement activatingagents, such as peptides or proteins comprising collagen-like domains orfibrinogen-like domains (e.g., a ficolin), carbohydrate-binding domains,and the like and combinations thereof. Additional active agents includethose useful in such compositions and methods including dopamine therapydrugs, catechol-O-methyl transferase (COMT) inhibitors, monamine oxidaseinhibitors, cognition enhancers (such as acetylcholinesterase inhibitorsor memantine), adenosine 2A receptor antagonists, beta-secretaseinhibitors, and gamma-secretase inhibitors. In particular embodiments,at least one compound of the present invention may be combined in apharmaceutical composition or a method of treatment with one or moredrugs selected from the group consisting of: tacrine (Cognex), donepezil(Aricept), rivastigmine (Exelon), galantamine (Reminyl), physostigmine,neostigmine, Icopezil (CP-118954,5,7-dihydro-3-(2-(1-(2-fluorobenzyl)-4-piperidinyl)ethyl)-6H-pyrrolo(3,2,f)-1,2-benzisoxazol-6-onemaleate), ER-127528(4-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl]methyl-1-(3-fluorobenzyl)piperidinehydrochloride), zanapezil (TAK-147;3-[1-(phenylmethyl)piperidin-4-yl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanefumarate), Metrifonate (T-588; (−)-R-α-[[2-(dimethylamino)ethoxy]methyl]benzo[b]thiophene-5-methanol hydrochloride), FK-960(N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide-hydrate), TCH-346(N-methyl-N-2-pyropinyldibenz[b,f]oxepine-10-methanamine), SDZ-220-581((S)-alpha-amino-5-(phosphonomethyl)-[1,1′-biphenyl]-3-propionic acid),memantine (Namenda/Exiba), 1,3,3,5,5-pentamethylcyclohexan-1-amine(Neramexane), tarenflurbil (Flurizan), tramiprosate (Alzhemed),clioquinol, PBT-2 (an 8-hydroxyquinilone derivative),1-(2-(2-Naphthyl)ethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine,Huperzine A, posatirelin, leuprolide or derivatives thereof,ispronicline, (3-aminopropyl)(n-butyl)phosphinic acid (SGS-742),N-methyl-5-(3-(5-isopropoxypyridinyl))-4-penten-2-amine (ispronicline),1-decanaminium, N-(2-hydroxy-3-sulfopropyl)-N-methyl-N-octyl-, innersalt (zt-1), salicylates, aspirin, amoxiprin, benorilate, cholinemagnesium salicylate, diflunisal, faislamine, methyl salicylate,magnesium salicylate, salicyl salicylate, diclofenac, aceclofenac,acemetacin, bromfenac, etodolac, indometacin, nabumetone, sulindac,tolmetin, ibuprofen, carprofen, fenbufen, fenoprofen, flurbiprofen,ketoprofen, ketorolac, loxoprofen, naproxen, tiaprofenic acid, suprofen,mefenamic acid, meclofenamic acid, phenylbutazone, azapropazone,metamizole, oxyphenbutazone, sulfinprazone, piroxicam, lornoxicam,meloxicam, tenoxicam, celecoxib, etoricoxib, lumiracoxib, parecoxib,rofecoxib, valdecoxib, nimesulide, arylalkanoic acids, 2-arylpropionicacids (profens), N-arylanthranilic acids (fenamic acids), pyrazolidinederivatives, oxicams, COX-2 inhibitors, sulphonanilides, essential fattyacids, and Minozac(2-(4-(4-methyl-6-phenylpyridazin-3-yl)piperazin-1-yl)pyrimidinedihydrochloride hydrate), and combinations thereof.

Potential combination agents for cancer therapies may include, forexample, protein and lipid kinase inhibitors (e.g., PI3K, B-raf,BCR/ABL), radiation treatment enhancers, microtubule binders (e.g.,taxol, vinblastine), cell metabolism inhibitors, DNA intercalators,topoisomerase inhibitors (e.g., doxorubicin), and DNA alkylating agents.

Assays

The compounds described herein can be used in research applications,including in in vitro, in vivo, or ex vivo experimental systems.Experimental systems can include, without limitation, cell samples,tissue samples, cell components or mixtures of cell components, whole orpartial organs, or organisms. Research applications include, withoutlimitation, use as assay reagents, elucidation of biochemical pathways,or evaluation of the effects of other agents on the experimental systemin the presence or absence of one or more compounds described herein.

The compounds described herein can also be used in biochemical assays.In some embodiments, a compound described herein can be incubated with atissue or cell sample from a subject to evaluate the subject's potentialresponse to administration of the compound, or to determine whichcompound described herein produces the optimum effect in a specificsubject or set of subjects. One such assay would involve (a) obtaining acell sample or tissue sample from a subject in which modulation of oneor more biomarkers can be assayed; (b) administering one or morecompounds described herein to the cell sample or tissue sample; and (c)determining the amount of modulation of the one or more biomarkers afteradministration of the compound, compared to the status of the biomarkerprior to administration of the compound. Optionally, following step (c),the assay would involve an additional step (d) selecting a compound foruse in treating a disease or medical condition associated with proteinaggregation based on the amount of modulation determined in step (c).

Chemical Synthesis

Exemplary chemical entities useful in methods of the invention will nowbe described by reference to illustrative synthetic schemes for theirgeneral preparation below and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Furthermore, one of skill in the art will recognizethat the transformations shown in the schemes below may be performed inany order that is compatible with the functionality of the particularpendant groups. Each of the reactions depicted in the general schemes ispreferably run at a temperature from about 0° C. to the refluxtemperature of the organic solvent used. Unless otherwise specified, thevariables are as defined above in reference to Formula (I) or (IA).Isotopically labeled compounds as described herein are preparedaccording to the methods described below, using suitably labeledstarting materials. Such materials are generally available fromcommercial suppliers of radiolabeled chemical reagents.

Certain compounds of Formula (I) or (IA) are prepared as shown in SchemeA. Substituted amino derivatives A1 are commercially available or areprepared according to known methods. Compounds A1 are coupled withactivated acyl compounds A2, wherein X is, for example, —OH or —Cl,under standard amide formation conditions to produce compounds ofFormula (I) or (IA). In alternative embodiments, A1 is coupled withX—C(O)-A-Hal, where Hal is, for example, bromo, and the bromosubstituent is displaced in a separate step with HNR³R⁴.

As shown in Scheme B, substituted indoles A1 are prepared frommethyl-indoles B1 by acylation followed by reductive amination. Thesemethods are also applicable to the preparation of derivatives where theR¹ ring is other than indole.

Heteroaryl compounds C4 are prepared according to Scheme C. Certaincompounds A, C1, A-CO₂R (where R is H or C₁₋₄alkyl), and C2 arecommercially available. In some embodiments, compounds A are halogenatedto form halo compounds C1, and then are acylated to formbis-functionalized compounds C2. In other embodiments, compounds A-CO₂Rare halogenated to form compounds C2. Coupling with amines HNR³R⁴ understandard amide coupling conditions provides compounds C3. Hydrolysis ofesters C3 yields amino acids C4, which can be used in coupling reactionsas shown in Scheme A. Suitable heterocyclic HNR³R⁴ intermediates such aspiperazines are commercially available or are prepared, for example, bycyclization of a suitably protected diamine, or by alkylation orreductive amination of a benzyl-protected piperazine derivative.

As shown in Scheme D, methyl-heterocyclic compounds D1 are homologatedwith, for example, paraformaldehyde, to provide hydroxyethyl compoundsD2. Activation of the hydroxyl group as, for example, a halide ortosylate, and displacement with HNR³R⁴, yields amino compounds D3.Acylation of the heterocyclic ring gives esters D4, and hydrolysisgenerates amino acids D5.

As shown in Scheme E, intermediates A1 may also be prepared using aHenry reaction to couple a heterocyclic aldehyde E1 with a suitablenitroalkane E2. Reduction of both the double bond and nitro groups (inone or two steps) provides amines A1.

As shown in Scheme F, substituted intermediates E1 may also be preparedby cyclization of a nitrophenyl derivative F1 with vinylmagnesiumbromide to form substituted indoles F2. Installation of a carbaldehydesubstituent at the 3-position of the indole may be accomplished, forexample, through a Vilsmaier-Haack reaction to give aldehydes E1.

EXAMPLES

The following examples are offered to illustrate but not to limit theinvention One of skill in the art will recognize that the followingsynthetic reactions and schemes may be modified by choice of suitablestarting materials and reagents in order to access other compounds ofFormula (I) or (IA).

Example 1:N-(1-(1H-Indol-3-yl)hexan-2-yl)-2-(4-ethylpiperazin-1-yl)thiazole-5-carboxamide

Step 1. Synthesis of 1-(1H-indol-3-yl)hexan-2-one

To a solution of 3-methylindole (12.0 g, 91.6 mmol) inN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (160mL) was added AlCl₃ (36.4 g, 274 mmol) at 0° C. The reaction mixture wasstirred at room temperature for 30 min. The reaction mixture was cooledto 0° C. followed by dropwise addition of pentanoyl chloride (8.00 g,124 mmol). The reaction mixture was stirred at room temperature for 16h. The reaction mixture was quenched with ice and extracted withdichloromethane (4×400 mL). The organic layer was separated, washed withbrine (200 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo.The crude obtained was purified by column chromatography (silica 100-200mesh, 10 to 30% EtOAc in hexanes) to afford 1-(1H-indol-3-yl)hexan-2-one(9.00 g, 50%) as a brown liquid. ¹H NMR (400 MHz, DMSO-d₆) δ 0.79 (t,J=7.3 Hz, 3H), 1.13-1.22 (m, 2H), 1.41 (m, 2H), 2.44-2.47 (m, 2H), 3.77(s, 2H), 6.94-7.01 (m, 1H), 7.07 (t, J=7.6 Hz, 1H), 7.23 (d, J=2.0 Hz,1H), 7.35 (d, J=7.8 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H), 10.93 (brs, 1H).

Step 2. Synthesis of 1-(1H-indol-3-yl)hexan-2-amine hydrochloride

To a solution of 1-(1H-indol-3-yl)hexan-2-one (12.0 g, 55.8 mmol) inmethanol (600 mL) was added NH₄OAc (36.3 g, 474 mmol) and the reactionmixture was stirred at 50° C. for 10 min. NaBH₃CN (4.20 g, 66.9 mmol)was added portion-wise and the reaction mixture was heated at reflux for12 h. The reaction mixture was acidified to pH 4 with 1 N HCl (50 mL)and concentrated in vacuo. The residue was diluted with H₂O (60 mL) andfiltered. The crude obtained was washed with hexane (3×20 mL) and driedin vacuo to afford 1-(1H-indol-3-yl)hexan-2-amine hydrochloride (10.5 g,75%) as a light yellow solid. LC/MS (ESI) m/e [M+H]⁺/RT (min)/%:216.95/4.8/96.6%. ¹H NMR (400 MHz, DMSO-d₆) δ 0.82 (t, J=7.1 Hz, 3H),1.12-1.34 (m, 4H), 1.41 (m, 1H), 1.54 (d, J=6.4 Hz, 2H), 2.86-2.98 (m,1H), 3.02-3.11 (m, 1H), 6.95-7.03 (m, 1H), 7.04-7.13 (m, 1H), 7.26 (s,1H), 7.37 (d, J=7.8 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 8.07 (brs, 3H),11.05 (brs, 1H).

Step 3. Synthesis ofN-(1-(1H-indol-3-yl)hexan-2-yl)-2-bromothiazole-5-carboxamide

To a solution of 1-(1H-indol-3-yl)hexan-2-amine hydrochloride (4.35 g,17.2 mmol) and 2-bromothiazole-5-carboxylic acid (3.59 g, 17.2 mmol) inN,N-dimethylformamide (DMF; 87 mL) was added 2-chloro-1methylpyridiniumiodide (Mukaiyama reagent; 7.45 g, 29.2 mmol) followed by addition ofN,N-diisopropylethylamine (DIPEA; 11.0 g, 86.0 mmol). The reactionmixture was stirred at room temperature for 16 h. The reaction mixturewas diluted with H₂O (50 mL) and extracted with dichloromethane (DCM;3×50 mL). The organic layer was separated, dried over anhydrous Na₂SO₄and concentrated in vacuo. The crude obtained was purified by columnchromatography (silica 230-400 mesh, 5 to 30% EtOAc in hexanes) andtriturating with petroleum ether and (10 mL) and pentane (25 mL) toafford N-(1-(1H-indol-3-yl)hexan-2-yl)-2-bromothiazole-5-carboxamide(3.30 g, 47%) as an off-white solid. MS (ESI) m/e [M+H]⁺/RT (min)/%:405.70/3.56/99.7%. ¹H NMR (400 MHz, DMSO-d₆) δ 0.81 (t, J=6.9 Hz, 3H),1.14-1.37 (m, 4H), 1.42-1.67 (m, 2H), 2.82-2.98 (m, 2H), 4.12 (d, J=4.1Hz, 1H), 6.91-6.99 (m, 1H), 7.04 (t, J=7.4 Hz, 1H), 7.11 (d, J=1.8 Hz,1H), 7.31 (d, J=8.3 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 8.22 (s, 1H), 8.51(d, J=8.3 Hz, 1H), 10.77 (brs, 1H).

Step 4

To a solution ofN-(1-(1H-indol-3-yl)hexan-2-yl)-2-bromothiazole-5-carboxamide (0.15 g,0.36 mmol) and 1-ethylpiperazine (0.05 g, 0.42 mmol) in CH₃CN (7.5 mL)was added K₂CO₃ (0.15 g, 0.11 mmol), and the reaction mixture was heatedin a sealed tube at 80° C. for 16 h. The reaction mixture wasconcentrated in vacuo. The residue was diluted with H₂O (10 mL) andextracted with 10% MeOH in DCM (10 mL). The organic layer was separated,dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crudeobtained was purified by triturating with Et₂O (10 mL), pentane (25 mL)and DCM (5 mL) to affordN-(1-(1H-indol-3-yl)hexan-2-yl)-2-(4-ethylpiperazin-1-yl)thiazole-5-carboxamide(0.10 g, 62%) as a light yellow solid. HPLC Purity: 99.3%. MS (ESI) m/e[M+H]⁺/RT (min)/%: 440.00/2.74/99.2%. ¹H NMR (400 MHz, DMSO-d₆) δ 0.81(t, J=6.9 Hz, 3H), 1.02 (t, J=7.1 Hz, 3H), 1.15-1.36 (m, 4H), 1.42-1.58(s, 2H), 2.37 (q, J=7.3 Hz, 2H), 2.46 (d, J=4.4 Hz, 4H), 2.77-2.94 (m,2H), 3.42-3.48 (m, 4H), 4.08-4.18 (m, 1H), 6.93-6.98 (m, 1H), 7.04 (t,J=7.3 Hz, 1H), 7.09 (s, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.57 (d, J=7.3 Hz,1H), 7.80 (s, 1H), 7.94 (d, J=8.3 Hz, 1H), 10.75 (brs, 1H).

Example 2:N-(1-(1H-Indol-3-yl)hexan-2-yl)-2-(4-isopropylpiperazin-1-yl)thiazole-5-carboxamide

To a solution ofN-(1-(1H-indol-3-yl)hexan-2-yl)-2-bromothiazole-5-carboxamide (0.20 g,0.49 mmol) and 1-isopropylpiperazine (0.07 g, 0.54 mmol) in CH₃CN (4.5mL) was added K₂CO₃ (0.20 g, 1.47 mmol) and the reaction mixture washeated at 80° C. for 16 h. The reaction mixture was concentrated invacuo. The residue was diluted with H₂O (10 mL) and extracted with 10%MeOH in DCM (10 mL). The organic layer was separated, dried overanhydrous Na₂SO₄ and concentrated in vacuo. The crude obtained waspurified by column chromatography (silica 230-400 mesh, 0 to 10% MeOH inDCM) and then triturating with petroleum ether (6 mL), pentane (10 mL),and DCM (2 mL) to affordN-(1-(1H-indol-3-yl)hexan-2-yl)-2-(4-isopropylpiperazin-1-yl)thiazole-5-carboxamide(0.16 g, 42%) as an off-white solid. HPLC Purity: 98.3%. LC/MS (ESI) m/e[M+H]⁺/RT (min)/%: 454.00/2.89/98.2.2%. ¹H NMR (400 MHz, DMSO-d₆) δ 0.81(t, J=6.9 Hz, 3H), 0.98 (d, J=6.4 Hz, 6H), 1.13-1.37 (m, 4H), 1.42-1.60(m, 2H), 2.66-2.75 (m, 1H), 2.76-2.95 (m, 2H), 3.40-3.48 (m, 4H),4.08-4.18 (m, 1H), 6.91-6.99 (m, 1H), 7.04 (t, J=7.3 Hz, 1H), 7.09 (brs,1H), 7.31 (d, J=8.3 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.80 (s, 1H), 7.93(d, J=8.3 Hz, 1H), 10.75 (brs, 1H) (4H's merged in solvent peak).

Example 3:N-(1-(1H-Indol-3-yl)hexan-2-yl)-2-(4-cyclopropylpiperazin-1-yl)thiazole-5-carboxamide

To a solution ofN-(1-(1H-indol-3-yl)hexan-2-yl)-2-bromothiazole-5-carboxamide (0.20 g,0.49 mmol) and 1-cyclopropylpiperazine (0.07 g, 0.54 mmol) in CH₃CN (4.5mL) was added K₂CO₃ (0.20 g, 1.47 mmol) and the reaction mixture washeated at 80° C. for 16 h. The reaction mixture was concentrated invacuo. The residue was diluted with H₂O (10 mL) and extracted with 10%MeOH in DCM (10 mL). The organic layer was separated, dried overanhydrous Na₂SO₄ and concentrated in vacuo. The crude obtained waspurified by column chromatography (silica 230-400 mesh, 0 to 10% MeOH inDCM) and then triturating with petroleum ether (6 mL), pentane (10 mL)and DCM (2 mL) to affordN-(1-(1H-indol-3-yl)hexan-2-yl)-2-(4-cyclopropylpiperazin-1-yl)thiazole-5-carboxamide(0.14 g, 63%) as an off-white solid. HPLC Purity: 99.0%. LC/MS (ESI) m/e[M+H]⁺/RT (min)/%: 452.00/2.91/98.8%. ¹H NMR (400 MHz, DMSO-d₆) δ0.35-0.44 (m, 4H), 0.82 (t, J=6.9 Hz, 3H), 1.16-1.37 (m, 4H), 1.40-1.60(m, 2H), 1.62-1.68 (m, 1H), 2.60-2.68 (m, 4H), 2.73-2.98 (m, 2H),3.40-3.48 (m, 4H), 4.04-4.18 (m, 1H), 6.92-6.99 (m, 1H), 7.04 (t, J=7.6Hz, 1H), 7.09 (s, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H),7.80 (s, 1H), 7.94 (d, J=8.8 Hz, 1H), 10.75 (brs, 1H).

Example 4:N-(1-(1H-Indol-3-yl)hexan-2-yl)-2-(4-(tert-butyl)piperazin-1-yl)thiazole-5-carboxamide

To a solution ofN-(1-(1H-indol-3-yl)hexan-2-yl)-2-bromothiazole-5-carboxamide (0.20 g,0.49 mmol) and 1-tert-butyl-piperazine (0.05 g, 0.54 mmol) in CH₃CN (4.5mL) was added K₂CO₃ (0.20 g, 1.47 mmol) and the reaction mixture washeated at 80° C. for 16 h. The reaction mixture was concentrated invacuo. The residue was diluted with H₂O (10 mL) and extracted with 10%MeOH in DCM (10 mL). The organic layer was separated, dried overanhydrous Na₂SO₄ and concentrated in vacuo. The crude obtained waspurified by column chromatography (silica 230-400 mesh, 0 to 10% MeOH inDCM) and then triturating with petroleum ether (6 mL), pentane (10 mL)and DCM (2 mL) to affordN-(1-(1H-indol-3-yl)hexan-2-yl)-2-(4-(tert-butyl)piperazin-1-yl)thiazole-5-carboxamide(0.15 g, 65%) as an off-white solid. HPLC Purity: 99.1%. LC/MS (ESI) m/e[M+H]⁺/RT (min)/%: 468.00/3.01/99.6%. ¹H NMR (400 MHz, DMSO-d₆) δ 0.81(t, J=6.8 Hz, 3H), 1.02 (s, 9H), 1.17-1.33 (m, 4H), 1.43-1.60 (m, 2H),2.59 (d, J=4.4 Hz, 4H), 2.74-2.97 (m, 2H), 3.37-3.44 (m, 4H), 4.04-4.16(m, 1H), 6.91-6.99 (m, 1H), 7.04 (t, J=7.6 Hz, 1H), 7.09 (d, J=1.5 Hz,1H), 7.31 (d, J=8.3 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.80 (s, 1H), 7.93(d, J=8.3 Hz, 1H), 10.75 (brs, 1H).

Example 5:N-(1-(1H-Indol-3-yl)hexan-2-yl)-2-(4-isobutylpiperazin-1-yl)thiazole-5-carboxamide

To a solution ofN-(1-(1H-indol-3-yl)hexan-2-yl)-2-bromothiazole-5-carboxamide (0.20 g,0.49 mmol) and 1-isobutylpiperazine (0.05 g, 0.54 mmol) in CH₃CN (4.5mL) was added K₂CO₃ (0.20 g, 1.47 mmol) and the reaction mixture washeated at 80° C. for 16 h. The reaction mixture was concentrated invacuo. The residue was diluted with H₂O (10 mL) and extracted with 10%MeOH in DCM (10 mL). The organic layer was separated, dried overanhydrous Na₂SO₄ and concentrated in vacuo. The crude obtained waspurified by column chromatography (silica 230-400 mesh, 0 to 10% MeOH inDCM) and then triturating with petroleum ether (6 mL), pentane (10 mL)and DCM (2 mL) to affordN-(1-(1H-indol-3-yl)hexan-2-yl)-2-(4-isobutylpiperazin-1-yl)thiazole-5-carboxamide(0.16 g, 69%) as an off-white solid. HPLC Purity: 97.4%. LC/MS (ESI) m/e[M+H]⁺/RT (min)/%: 468.00/3.33/99.52%. ¹H NMR (400 MHz, DMSO-d₆) δ 0.81(t, J=6.8 Hz, 3H), 0.87 (d, J=6.4 Hz, 6H), 1.13-1.37 (m, 4H), 1.42-1.58(m, 2H), 1.76-1.82 (m, 1H), 2.08 (d, J=6.8 Hz, 2H), 2.40-2.48 (m, 4H),2.73-2.95 (m, 2H), 3.42-3.48 (m, 4H), 4.10-4.18 (m, 1H), 6.92-6.99 (m,1H), 7.04 (t, J=7.3 Hz, 1H), 7.09 (brs, 1H), 7.31 (d, J=8.3 Hz, 1H),7.57 (d, J=7.3 Hz, 1H), 7.80 (s, 1H), 7.94 (d, J=8.8 Hz, 1H), 10.75(brs, 1H).

Example 6:N-(1-(1H-Indol-3-yl)hexan-2-yl)-2-(4-(2-methoxyethyl)piperazin-1-yl)thiazole-5-carboxamide

Step 1: Synthesis of 1-(2-methoxyethyl)piperazine hydrochloride

To a solution of tert-butyl piperazine-1-carboxylate (5.00 g, 26.8 mmol)in CH₃CN (50 mL) was added K₂CO₃ (3.70 g, 26.8 mmol) and KI (4.40 g,26.8 mmol) in sealed tube, followed by addition of1-bromo-2-methoxyethane (4.10 g, 29.5 mmol). The reaction mixture washeated at 80° C. for 16 h. The reaction mixture was diluted with EtOAc(100 mL) and washed with H₂O (2×25 mL). The organic layer was separated,washed with brine (50 mL), dried over anhydrous Na₂SO₄ and concentratedin vacuo. The residue was triturated with pentane (20 mL) and dissolvedin dioxane (25 mL). Dioxane*HCl (20 mL) was added at 0° C., and thereaction mixture was stirred at room temperature for 16 h. The reactionmixture was cooled to 10° C. and filtered. The residue was washed withDCM (5 mL) and dried in vacuo to afford 1-(2-methoxyethyl)piperazinehydrochloride (3.00 g, 79%) as a white solid. LC/MS (ESI) m/e [M+H]⁺/RT(min)/%: 145.00/1.39/97.4%. ¹H NMR (400 MHz, DMSO-d₆) δ 3.28 (s, 3H),3.43-3.63 (m, 10H), 3.73 (t, J=4.4 Hz, 2H), 9.99 (brs, 1H), 11.94 (brs,1H).

Step 2

The title compound was prepared from 0.20 g (0.49 mmol) ofN-(1-(1H-indol-3-yl)hexan-2-yl)-2-bromothiazole-5-carboxamide and 0.10 g(0.54 mmol) of 1-(2-methoxyethyl)piperazine hydrochloride using themethod described for Example 1. The productN-(1-(1H-indol-3-yl)hexan-2-yl)-2-(4-(2-methoxyethyl)piperazin-1-yl)thiazole-5-carboxamidewas obtained as an off-white solid (0.16 g, 69%). HPLC Purity: 99.5%.LC/MS (ESI) m/e [M+H]⁺/RT (min)/%: 470.00/3.33/99.5%. ¹H NMR (400 MHz,DMSO-d₆) δ 0.81 (t, J=6.8 Hz, 3H), 1.16-1.60 (m, 6H), 2.80-2.94 (m, 2H),3.24 (s, 3H), 3.38-3.53 (m, 6H), 4.06-1.16 (m, 1H), 6.97 (d, J=7.3 Hz,1H), 7.05 (t, J=7.1 Hz, 1H), 7.10 (brs, 1H), 7.31 (d, J=7.8 Hz, 1H),7.58 (d, J=7.3 Hz, 1H), 7.81 (brs, 1H), 7.94 (d, J=7.8 Hz, 1H), 10.76(brs, 1H) (6H's merged in solvent peak).

Example 7:N-(1-(1H-Indol-3-yl)hexan-2-yl)-2-(4-(2-fluoroethyl)piperazin-1-yl)thiazole-5-carboxamide

Step 1: Synthesis of 1-(2-fluoroethyl)piperazine hydrochloride

To a solution of tert-butyl piperazine-1-carboxlate (2.50 g, 13.4 mmol)in CH₃CN (45 mL) was added K₂CO₃ (4.62 g, 33.0 mmol) in sealed tubefollowed by addition of 1-fluoro-2-iodoethane (2.53 g, 20.1 mmol). Thereaction mixture was heated at 80° C. for 14 h. The reaction mixture wasdiluted with EtOAc (200 mL) and washed with H₂O (100 mL). The organiclayer was separated, washed with brine (20 mL), dried over anhydrousNa₂SO₄ and concentrated in vacuo. To the residue was added dioxane*HCl(100 mL) dropwise at 10° C. and the reaction mixture was stirred at roomtemperature for 4 h. The reaction mixture was cooled to 10° C. andfiltered. The residue was washed with hexane (2×10 mL) and dried invacuo to afford 1-(2-fluoroethyl)piperazine hydrochloride (1.75 g, 77%)as a white solid. MS (ESI) m/e [M+H]⁺/RT (min)/%: 133.00/2.69/99.6%. ¹HNMR (400 MHz, DMSO-d₆) δ 3.46-3.63 (m, 8H), 4.84 (t, J=4.4 Hz, 2H), 4.96(t, J=4.0 Hz, 2H), 10.02 (brs, 1H), 12.37 (brs, 1H).

Step 2

The title compound was prepared fromN-(1-(1H-indol-3-yl)hexan-2-yl)-2-bromothiazole-5-carboxamide and1-(2-fluoroethyl)piperazine using the method described for Example 1.The crude obtained was purified by column chromatography (silica 230-400mesh, 0.5 to 3.5% MeOH in DCM) and then triturating with pentane (10 mL)to affordN-(1-(1H-indol-3-yl)hexan-2-yl)-2-(4-(2-fluoroethyl)piperazin-1-yl)thiazole-5-carboxamide(0.12 g, 53%) as a white solid. HPLC Purity: 99.4%. MS (ESI) m/e[M+H]⁺/RT (min)/%: 58.00/2.80/99.3%. ¹H NMR (400 MHz, DMSO-d₆) δ 0.80(t, J=6.8 Hz, 3H), 1.13-1.32 (m, 4H), 1.39-1.63 (m, 2H), 2.53-2.59 (m,4H), 2.64 (t, J=4.9 Hz, 1H), 2.71 (t, J=4.9 Hz, 1H), 2.77-2.92 (m, 2H),3.41-3.52 (m, 4H), 4.08-4.16 (m, 1H), 4.50 (t, J=4.9 Hz, 1H), 4.62 (t,J=4.9 Hz, 1H), 6.91-6.99 (m, 1H), 7.04 (t, J=7.1 Hz, 1H), 7.09 (d, J=2.0Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.81 (s, 1H),7.95 (d, J=8.3 Hz, 1H), 10.76 (s, 1H).

Example 8:N-(1-(1H-Indol-3-yl)hexan-2-yl)-2-(4-(2,2-difluoroethyl)piperazin-1-yl)thiazole-5-carboxamide

Step 1: Synthesis of 1-(2,2-difluoroethyl)piperazine

To a solution of 2,2-difluoroethan-1-ol (0.53 g, 6.40 mmol) in DCM (10mL) was added a solution of triethylamine (0.98 g, 9.60 mmol) andO(SO₂CF₃)₂ (2.10 g, 7.50 mmol) at 0° C. and stirred at same temperaturefor 30 min. A solution of tert-butyl piperazine-1-carboxylate (1.00 g,5.37 mmol) in DCM (16 mL) was added at 0° C. and the reaction mixturewas stirred at room temperature for 16 h. The reaction mixture wasdiluted with H₂O (30 mL). The organic layer was separated, washed withbrine (50 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo.The residue was dissolved in dioxane (15 mL) followed by addition ofdioxane*HCl (15 mL) at 0° C. and the reaction mixture was stirred atroom temperature for 5 h. The reaction mixture was cooled to 0° C. andfiltered. The residue was washed with pentane (20 mL) and dried in vacuoto afford 1-(2,2-difluoroethyl)piperazine (0.70 g, 69%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 3.20-3.40 (m, 10H), 6.27-6.55 (m,1H), 9.66 (brs, 1H).

Step 2

To a solution ofN-(1-(1H-indol-3-yl)hexan-2-yl)-2-bromothiazole-5-carboxamide (0.20 g,0.49 mmol) and 1-(2,2-difluoroethyl)piperazine (0.11 g, 0.58 mmol) inCH₃CN (4.5 mL) was added K₂CO₃ (0.20 g, 1.47 mmol) and the reactionmixture was heated at 80° C. for 16 h. The reaction mixture wasconcentrated in vacuo. The residue was diluted with H₂O (10 mL) andextracted with 10% MeOH in DCM (3×20 mL). The organic layer wasseparated, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Thecrude obtained was purified by column chromatography (silica 230-400mesh, 0.5 to 5% MeOH in DCM) and triturated with pentane (3×5 mL) toaffordN-(1-(1H-indol-3-yl)hexan-2-yl)-2-(4-(2,2-difluoroethyl)piperazin-1-yl)thiazole-5-carboxamide(0.135 g, 58%) as an off-white solid. HPLC Purity: 99.5%. MS (ESI) m/e[M+H]⁺/RT (min)/%: 476.00/2.89/99.2%. ¹H NMR (400 MHz, DMSO-d₆) δ 0.81(t, J=6.8 Hz, 3H), 1.16-1.32 (m, 4H), 1.44-1.60 (m, 2H), 2.58-2.67 (m,4H), 2.73-2.96 (m, 4H), 3.40-3.50 (m, 4H), 4.04-4.18 (m, 1H), 5.95-6.37(m, 1H), 6.92-6.98 (m, 1H), 7.04 (t, J=7.1 Hz, 1H), 7.09 (d, J=2.0 Hz,1H), 7.31 (d, J=7.8 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.81 (s, 1H), 7.95(d, J=8.3 Hz, 1H), 10.75 (brs, 1H).

Example 9:N-(1-(1H-Indol-3-yl)hexan-2-yl)-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)thiazole-5-carboxamide

Step 1: Synthesis of tert-butyl4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate

To a solution of trifluoroethanol (0.32 g, 3.22 mmol) in DCM (10 mL) wasadded a solution of triethylamine (0.65 g, 4.82 mmol) andtrifluoromethanesulfonic anhydride (1.05 g, 3.75 mmol) at 0° C. andstirred at same temperature for 30 min. A solution of tert-butylpiperazine-1-carboxylate (0.50 g, 2.68 mmol) in DCM (10 mL) was addedand the reaction mixture was stirred at room temperature for 16 h. Thereaction mixture was diluted with H₂O (20 mL). The organic layer wasseparated, washed with H₂O (20 mL), dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The crude obtained was purified by columnchromatography (silica 100-200 mesh, 0.5 to 2% MeOH in DCM) to affordtert-butyl 4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate (0.40 g,55%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.46 (s, 9H),2.64-2.58 (m, 4H), 2.92-3.04 (m, 2H), 3.48-3.36 (m, 4H).

Step 2: Synthesis of 1-(2,2,2-trifluoroethyl)piperazine

To a solution of tert-butyl4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate (0.40 g, 1.49 mmol) indioxane (9 mL) was added 4 N HCl in dioxane (10 mL) at 0° C. and thereaction mixture was stirred at room temperature for 4 h. The reactionmixture was cooled to 0 to 5° C., filtered, and washed with hexane (20mL). The crude obtained was purified by triturating with pentane (20 mL)to afford 1-(2,2,2-trifluoroethyl)piperazine (0.15 g, 60%) as a greysemi-solid. ¹H NMR (400 MHz, DMSO-d₆) δ 2.88-2.81 (m, 4H), 3.02-3.12 (m,4H), 3.24-3.38 (m, 2H), 9.15 (s, 1H).

Step 3

To a solution ofN-(1-(1H-indol-3-yl)hexan-2-yl)-2-bromothiazole-5-carboxamide (0.20 g,0.49 mmol) and 1-(2,2,2-trifluoroethyl)piperazine (0.11 g, 0.54 mmol) inCH₃CN (4.5 mL) was added K₂CO₃ (0.20 g, 1.47 mmol) and the reactionmixture was heated at 80° C. for 16 h. The reaction mixture wasconcentrated in vacuo. The residue was diluted with H₂O (10 mL) andextracted with 10% MeOH in DCM (10 mL). The organic layer was separated,dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crudeobtained was purified by column chromatography (silica 230-400 mesh, 0.5to 3.5% MeOH in DCM) and then triturating pentane (10 mL) to affordN-(1-(1H-indol-3-yl)hexan-2-yl)-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)thiazole-5-carboxamide(0.17 g, 70%) as an off-white solid. HPLC Purity: 97.9%. MS (ESI) m/e[M+H]⁺/RT (min)/%: 494.00/3.09/98.2%. ¹H NMR (400 MHz, DMSO-d₆) 0.81 (t,J=6.9 Hz, 3H), 1.12-1.37 (m, 4H), 1.44-1.62 (m, 2H), 2.64-2.74 (m, 4H),2.78-2.97 (m, 2H), 3.30-3.20 (m, 2H), 3.44-3.52 (m, 4H), 4.06-4.18 (m,1H), 6.92-6.99 (m, 1H), 7.04 (t, J=7.3 Hz, 1H), 7.09 (brs, 1H), 7.31 (d,J=7.8 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.81 (s, 1H), 7.95 (d, J=8.3 Hz,1H), 10.75 (brs, 1H).

Example 10:N-(1-(1H-Indol-3-yl)hexan-2-yl)-2-(4-(3,3,3-trifluoropropyl)piperazin-1-yl)thiazole-5-carboxamide

Step 1. Synthesis of 1-(3,3,3-trifluoropropyl)piperazine

To a solution of tert-butyl piperazine-1-carboxylate (0.50 g, 2.60 mmol)in CH₃CN (20 mL) was added K₂CO₃ (0.92 g, 6.70 mmol) followed byaddition of 1,1,1-trifluoro-3-iodopropane (0.90 g, 4.00 mmol). Thereaction mixture was heated at 80° C. for 14 h. The reaction mixture wasdiluted with EtOAc (200 mL) and washed with H₂O (100 mL). The organiclayer was separated, washed with brine (10 mL), dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was dissolved in dioxane(20 mL), and 4 M HCl in dioxane (20 mL) was added drop wise at 5° C. Thereaction mixture was stirred at room temperature for 6 h. The reactionmixture was cooled to 0° C. and filtered. The residue was washed withpentane (20 mL) and dried in vacuo to afford1-(3,3,3-trifluoropropyl)piperazine (0.40 g, 68%) as an off-white solid.MS (ESI) m/e [M+H]⁺/RT (min)/%: 183.00/1.91/96.5%.

Step 2

To a solution ofN-(1-(1H-indol-3-yl)hexan-2-yl)-2-bromothiazole-5-carboxamide (0.20 g,0.49 mmol) and 1-(3,3,3-trifluoropropyl)piperazine (0.13 g, 0.58 mmol)in CH₃CN (4.5 mL) was added K₂CO₃ (0.20 g, 1.47 mmol), and the reactionmixture was heated at 80° C. for 16 h. The reaction mixture wasconcentrated in vacuo. The residue was diluted with H₂O (10 mL) andextracted with 10% MeOH in DCM (3×10 mL). The organic layer wasseparated, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Thecrude obtained was purified by column chromatography (silica 230-400mesh, 0.5 to 5% MeOH in DCM) and triturated with pentane (3×5 mL) toaffordN-(1-(1H-indol-3-yl)hexan-2-yl)-2-(4-(3,3,3-trifluoropropyl)piperazin-1-yl)thiazole-5-carboxamide(0.10 g, 40%) as an off-white solid. HPLC Purity: 99.2%. MS (ESI) m/e[M+H]⁺/RT (min)/%: 508.00/3.28/98.1%. ¹H NMR (400 MHz, DMSO-d₆) δ 0.81(t, J=6.8 Hz, 3H), 1.16-1.30 (m, 4H), 1.46-1.57 (m, 2H), 2.56-2.61 (m,2H), 2.77-2.93 (m, 2H), 3.39-3.48 (m, 4H), 4.06-4.18 (m, 1H), 6.92-6.98(m, 1H), 7.04 (t, J=7.3 Hz, 1H), 7.09 (d, J=2.0 Hz, 1H), 7.31 (d, J=8.3Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.81 (s, 1H), 7.95 (d, J=8.3 Hz, 1H),10.76 (brs, 1H) (6H's merged in solvent peak).

Example 11:N-(1-(1H-Indol-3-yl)hexan-2-yl)-2-(3,4-dimethylpiperazin-1-yl)thiazole-5-carboxamide

To a solution ofN-(1-(1H-indol-3-yl)hexan-2-yl)-2-bromothiazole-5-carboxamide (0.20 g,0.49 mmol) and 1,2-dimethylpiperazine (0.06 g, 0.54 mmol) in CH₃CN (4.5mL) was added K₂CO₃ (0.20 g, 1.47 mmol) and the reaction mixture washeated at 80° C. for 16 h. The reaction mixture was concentrated invacuo. The residue was diluted with H₂O (10 mL) and extracted with 10%MeOH in DCM (10 mL). The organic layer was separated, dried overanhydrous Na₂SO₄ and concentrated in vacuo. The crude obtained waspurified by column chromatography (silica 230-400 mesh, 0.5 to 3.5% MeOHin DCM) and triturating with pentane (10 mL) to affordN-(1-(1H-indol-3-yl)hexan-2-yl)-2-(3,4-dimethylpiperazin-1-yl)thiazole-5-carboxamide (0.075g, 34%) as a white solid. HPLC Purity: 99.2%. LC/MS (ESI) m/e [M+H]⁺/RT(min)/%: 440.00/2.76/99.8%. ¹H NMR (400 MHz, DMSO-d₆) δ 0.81 (t, J=6.9Hz, 3H), 1.02 (d, J=6.4 Hz, 3H), 1.18-1.31 (m, 4H), 1.40-1.60 (m, 2H),2.06-2.18 (m, 2H), 2.20 (s, 3H), 2.69-2.91 (m, 4H), 3.10-3.22 (m, 1H),3.64-3.77 (m, 2H), 4.11 (d, J=4.4 Hz, 1H), 6.91-6.99 (m, 1H), 7.04 (t,J=7.6 Hz, 1H), 7.09 (brs, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.57 (d, J=7.8Hz, 1H), 7.80 (s, 1H), 7.93 (d, J=8.3 Hz, 1H), 10.75 (brs, 1H).

Example 12:N-(1-(1H-Indol-3-yl)hexan-2-yl)-2-(3,3,4-trimethylpiperazin-1-yl)thiazole-5-carboxamide

Step 1: Synthesis of 3,3-dimethylpiperazin-2-one

To a solution of 1,2-diaminoethane (7.70 g, 128 mmol) in toluene (55 mL)was added a solution of ethyl 2-bromo-2-methylpropanoate (5.00 g, 25.6mmol) in toluene (5 mL) dropwise at 0° C., and the reaction mixture wasstirred at room temperature for 1 h and then at reflux for 16 h. Thereaction mixture was extracted with toluene (30 mL). The organic layerwas separated, dried over anhydrous Na₂SO₄ and concentrated in vacuo.The crude obtained was purified by column chromatography (silica 100-200mesh, 2 to 10% methanolic NH₃ in DCM) to afford3,3-dimethylpiperazin-2-one (2.81 g, 87%) as an off-white solid. LC/MS(ESI) m/e [M+H]⁺/RT (min)/%: 128.90/0.61/69.8%. ¹H NMR (400 MHz,DMSO-d₆) δ 1.15 (s, 6H), 2.24 (s, 1H), 2.80-2.86 (m, 2H), 3.10-3.16 (m,2H), 7.35 (s, 1H).

Step 2: Synthesis of 3,3,4-trimethylpiperazin-2-one

To a solution of 3,3-dimethylpiperazin-2-one (1.50 g, 11.7 mmol) in DCM(20 mL) was added a 37% HCHO solution (0.48 mL, 17.5 mmol) dropwise at0° C. followed by portion-wise addition of Na(OAc)₃BH (3.22 g, 15.2mmol). The reaction mixture was stirred at room temperature for 3 h. Thereaction mixture was diluted with DCM (100 mL) and washed with satd. aq.NaHCO₃ (100 mL). The organic layer was separated, dried over anhydrousNa₂SO₄ and concentrated in vacuo to afford3,3,4-trimethylpiperazin-2-one (0.85 g crude) as a white solid. Thiscompound was used as such for the next reaction without furtherpurification. LC/MS (ESI) m/e [M+H]⁺/RT (min)/%: 142.85/0.46/99.7%.

Step 3: Synthesis of 1,2,2-trimethylpiperazine

To a solution of 3,3,4-trimethylpiperazin-2-one (0.83 g, 5.84 mmol) intetrahydrofuran (THF; 25 mL) was added lithium aluminum hydride (LAH)(0.17 g, 4.47 mmol) portion-wise at 0° C., and the reaction mixture washeated at reflux for 4.5 h. The reaction mixture was quenched with coldaq. NH₄Cl (20 mL) and extracted with DCM (3×25 mL). The organic layerwas separated, dried over anhydrous Na₂SO₄ and concentrated in vacuo.The crude obtained was purified by triturating with pentane (10 mL) andEt₂O (3 mL) to afford 1,2,2-trimethylpiperazine (0.31 g crude) as a greysolid. LC/MS (ESI) m/e [M+H]⁺/RT (min)/%: 129.00/2.50/86.5%. ¹H NMR (400MHz, DMSO-d₆) δ 0.90 (s, 6H), 1.55 (s, 1H), 2.02 (s, 3H), 2.21-2.29 (m,2H), 2.35 (s, 2H), 2.60-2.66 (m, 2H).

Step 4

To a solution ofN-(1-(1H-indol-3-yl)hexan-2-yl)-2-bromothiazole-5-carboxamide (0.20 g,0.49 mmol) and 1,2,2-trimethylpiperazine (0.07 g, 0.54 mmol) in CH₃CN(4.5 mL) was added K₂CO₃ (0.20 g, 1.47 mmol), and the reaction mixturewas heated at 80° C. for 16 h. The reaction mixture was concentrated invacuo. The residue was diluted with H₂O (3×10 mL) and extracted with 10%MeOH in DCM (3×20 mL). The organic layer was separated, dried overanhydrous Na₂SO₄ and concentrated in vacuo. The crude obtained waspurified by column chromatography (silica 230-400 mesh, 0.5 to 5% MeOHin DCM) and triturated with pentane (3×5 mL) to affordN-(1-(1H-indol-3-yl)hexan-2-yl)-2-(3,3,4-trimethylpiperazin-1-yl)thiazole-5-carboxamide(0.09 g, 41%) as an off-white solid. HPLC Purity: 98.9%. LC/MS (ESI) m/e[M+H]⁺/RT (min)/%: 454.00/2.75/99.2%. ¹H NMR (400 MHz, DMSO-d₆) δ 0.81(t, J=6.9 Hz, 3H), 0.97 (s, 6H), 1.17-1.31 (m, 6H), 1.44-1.60 (m, 2H),2.15 (s, 3H), 2.74-2.96 (m, 2H), 3.20 (s, 2H), 3.42-3.48 (m, 2H),4.08-4.18 (m, 1H), 6.93-6.98 (m, 1H), 7.04 (t, J=7.3 Hz, 1H), 7.09 (s,1H), 7.31 (d, J=7.8 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.77 (s, 1H), 7.91(d, J=8.3 Hz, 1H), 10.75 (brs, 1H).

Example 13:N-(1-(1H-Indol-3-yl)hexan-2-yl)-2-(cis-3,4,5-trimethylpiperazin-1-yl)thiazole-5-carboxamide

Step 1: Synthesis of tert-butyl cis-3,5-dimethylpiperazine-1-carboxylate

To a solution of cis-2,6-dimethylpiperazine (1.00 g, 8.70 mmol) in CHCl₃(20 mL) was added Boc anhydride (1.90 g, 8.70 mmol) drop-wise at 0° C.,and the reaction mixture was stirred at room temperature for 16 h. Thereaction mixture was diluted with DCM (30 mL) and washed with H₂O (30mL). The organic layer was separated, washed with brine (10 mL), driedover anhydrous Na₂SO₄ and concentrated in vacuo to afford tert-butylcis-3,5-dimethylpiperazine-1-carboxylate (1.82 g crude) as an off-whitesolid. This compound was used as such for the next reaction withoutfurther purification. LC/MS (ESI) m/e [M+H]⁺/RT (min)/%:215.00/2.52/83.4%. ¹H NMR (400 MHz, DMSO-d₆) δ 1.05 (d, J=6.1 Hz, 6H),1.20 (d, J=6.7 Hz, 1H), 1.46 (s, 9H), 2.32-2.40 (m, 2H), 2.72-2.82 (m,2H), 3.80-4.02 (m, 2H).

Step 2: Synthesis of tert-butylcis-3,4,5-trimethylpiperazine-1-carboxylate

To a solution of tert-butyl cis-3,5-dimethylpiperazine-1-carboxylate(1.80 g, 8.40 mmol) in DCM (20 mL) was added a 37% HCHO solution (0.34mL, 12.0 mmol) dropwise at 0° C., followed by portion-wise addition ofNa(OAc)₃BH (2.31 g, 10.9 mmol). The reaction mixture was stirred at roomtemperature for 4 h. The reaction mixture was diluted with DCM (30 mL)and washed with NaHCO₃ (20 mL) solution. The organic layer wasseparated, washed with brine (20 mL), dried over anhydrous Na₂SO₄ andconcentrated in vacuo to afford tert-butylcis-3,4,5-trimethylpiperazine-1-carboxylate (1.81 g crude) as acolorless liquid. This compound was used as such for the next reactionwithout further purification. LC/MS (ESI) m/e [M+H]⁺/RT (min)/%:228.90/4.29/88.5%. ¹H NMR (400 MHz, CDCl₃) δ 1.08 (d, J=6.1 Hz, 6H),1.48 (s, 9H), 2.04-2.18 (m, 2H), 2.26 (s, 3H), 2.56-2.62 (m, 2H),3.78-3.98 (m, 2H).

Step 3: Synthesis of cis-1,2,6-trimethylpiperazine

To a solution of tert-butyl cis-3,4,5-trimethylpiperazine-1-carboxylate(1.80 g, 7.89 mmol) in dioxane (10 mL) was added 4 M HCl in dioxane (15mL) at 0° C., and the reaction mixture was stirred at room temperaturefor 16 h. The reaction mixture was cooled to 0 to 10° C., filtered,washed with pentane (20 mL) and dried in vacuo to affordcis-1,2,6-trimethylpiperazine (1.40 g crude) as a colorless semi-solid.This compound was used as such for the next reaction without furtherpurification. LC/MS (ESI) m/e [M+H]⁺/RT (min)/%: 128.85/1.58/88.8%.

Step 4

To a solution ofN-(1-(1H-indol-3-yl)hexan-2-yl)-2-bromothiazole-5-carboxamide (0.20 g,0.49 mmol) and cis-1,2,6-trimethylpiperazine (0.09 g, 0.54 mmol) inCH₃CN (4.5 mL) was added K₂CO₃ (0.20 g, 1.47 mmol) and the reactionmixture was heated at 80° C. for 16 h. The reaction mixture wasconcentrated in vacuo. The residue was diluted with H₂O (10 mL) andextracted with 10% MeOH in DCM (3×10 mL). The organic layer wasseparated, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Thecrude obtained was purified by column chromatography (silica 230-400mesh, 0.5 to 5% MeOH in DCM) and triturated with pentane (3×5 mL) toaffordN-(1-(1H-indol-3-yl)hexan-2-yl)-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)thiazole-5-carboxamide(0.09 g, 41%) as an off-white solid. HPLC Purity: 99.8%. LC/MS (ESI) m/e[M+H]⁺/RT (min)/%: 454.00/3.07/96.5%. ¹H NMR (400 MHz, DMSO-d₆) δ 0.81(t, J=6.8 Hz, 3H), 1.05 (d, J=5.9 Hz, 6H), 1.16-1.37 (m, 4H), 1.41-1.63(m, 2H), 2.16 (s, 3H), 2.18-2.24 (m, 2H), 2.73-2.92 (m, 4H), 3.72 (d,J=11.2 Hz, 2H), 4.06-4.18 (m, 1H), 6.93-6.98 (m, 1H), 7.04 (t, J=7.3 Hz,1H), 7.09 (d, J=2.0 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.57 (d, J=7.8 Hz,1H), 7.79 (s, 1H), 7.94 (d, J=8.8 Hz, 1H), 10.76 (brs, 1H).

Example 14:N-(1-(1H-Indol-3-yl)-5-methylhexan-2-yl)-(4-methylpiperazin-1-yl)thiazole-5-carboxamide

Step 1: Synthesis of 1-(1H-indol-3-yl)-5-methylhexan-2-one

To a solution of 3-methylindole (0.50 g, 3.80 mmol) in dichloroethane(20 mL) was added AlCl₃ (1.50 g, 11.2 mmol) at 0° C., and the reactionwas stirred at 0° C. for 10 min and then at room temperature for 30 min.The reaction mixture was cooled to 0° C. followed by dropwise additionof 4-methylpentanoyl chloride (0.58 g, 4.32 mmol). The reaction mixturewas stirred at room temperature for 16 h. The reaction mixture wasquenched with ice H₂O (50 mL) and extracted with DCM (2×50 mL). Theorganic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The crude obtained was purified by columnchromatography (silica 100-200 mesh, 1 to 10% EtOAc in hexanes) toafford 1-(1H-indol-3-yl)-5-methylhexan-2-one (0.33 g, 38%) as a yellowliquid. MS (ESI) m/e [M+H]⁺/RT (min)/%: 229.95/3.39/85.4%. ¹H NMR (400MHz, DMSO-d₆) δ 0.77 (d, J=6.5 Hz, 6H), 1.30-1.44 (m, 3H), 2.46 (t,J=7.5 Hz, 2H), 3.78 (s, 2H), 6.97 (t, J=7.3 Hz, 1H), 7.06 (t, J=7.3 Hz,1H), 7.23 (d, J=2.0 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.42 (d, J=7.8 Hz,1H), 10.93 (s, 1H).

Step 2: Synthesis of 1-(1H-indol-3-yl)-5-methylhexan-2-aminehydrochloride

To a solution of 1-(1H-indol-3-yl)-5-methylhexan-2-one (0.32 g, 1.40mmol) in MeOH (25 mL) was added NH₄OAc (0.92 g, 11.9 mmol), and thereaction mixture was stirred at 50° C. for 10 min. NaBH₃CN (0.10 g, 1.68mmol) was added portion-wise, and the reaction mixture was heated atreflux for 16 h. The reaction mixture was concentrated in vacuo. Theresidue was triturated with 3 N HCl (10 mL) and H₂O (5 mL). The crudeobtained was washed with hexanes (20 mL) and pentane (10 mL) to afford1-(1H-indol-3-yl)-5-methylhexan-2-amine hydrochloride (0.285 g, 75%) asa light yellow solid. MS (ESI) m/e [M+H]⁺/RT (min)/%: 231.00/3.7/96.4%.¹H NMR (400 MHz, DMSO-d₆) δ 0.80 (d, J=6.5 Hz, 6H), 1.18-1.60 (m, 5H),2.90-3.04 (m, 2H), 3.24-3.34 (m, 1H), 6.95 (t, J=7.4 Hz, 1H), 7.04 (t,J=7.4 Hz, 1H), 7.25 (s, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.57 (d, J=7.7 Hz,1H), 7.93 (brs, 2H), 11.00 (brs, 1H)

Step 3: Synthesis ofN-(1-(1H-indol-3-yl)-5-methylhexan-2-yl)-2-bromothiazole-5-carboxamide

To a solution of 1-(1H-indol-3-yl)-5-methylhexan-2-amine hydrochloride(0.28 g, 1.04 mmol) and 2-bromothiazole-5-carboxylic acid (0.20 g, 1.25mmol) in DMF (15 mL) was added Mukaiyama reagent (0.45 g, 1.77 mmol)followed by addition of DIPEA (0.68 g, 5.27 mmol). The reaction mixturewas stirred at room temperature for 5 h. The reaction mixture wasdiluted with H₂O (60 mL) and extracted with DCM (3×20 mL). The organiclayer was separated, dried over anhydrous Na₂SO₄ and concentrated invacuo. The crude obtained was purified by column chromatography (silica230-400 mesh, 5 to 25% EtOAc in hexanes) to affordN-(1-(1H-indol-3-yl)-5-methylhexan-2-yl)-2-bromothiazole-5-carboxamide(0.29 g, 66%) as a yellow semi solid. MS (ESI) m/e [M+H+1]⁺/RT (min)/%:422.00/3.7/95.9%. ¹H NMR (400 MHz, DMSO-d₆) δ 0.80 (d, J=6.4 Hz, 6H),1.14-1.24 (m, 2H), 1.42-1.61 (m, 3H), 2.89 (d, J=6.4 Hz, 2H), 4.06-4.14(m, 1H), 6.95 (t, J=7.4 Hz, 1H), 7.04 (t, J=7.4 Hz, 1H), 7.12 (s, 1H),7.31 (d, J=8.1 Hz, 1H), 7.56 (d, J=7.4 Hz, 1H), 8.21 (s, 1H), 8.50 (d,J=8.8 Hz, 1H), 10.77 (s, 1H).

Step 4

To a solution ofN-(1-(1H-indol-3-yl)-5-methylhexan-2-yl)-2-bromothiazole-5-carboxamide(0.28 g, 0.66 mmol) and 1-methylpiperazine (0.10 g, 0.99 mmol) in CH₃CN(5 mL) was added K₂CO₃ (0.27 g, 1.90 mmol), and the reaction mixture washeated at 80° C. for 16 h. The reaction mixture was concentrated invacuo. The residue was diluted with H₂O (20 mL) and extracted with 10%MeOH in DCM (3×20 mL). The organic layer was separated, dried overanhydrous Na₂SO₄ and concentrated in vacuo. The crude obtained waspurified by column chromatography (silica 230-400 mesh, 2 to 10% MeOH inDCM) and triturated with pentane (2×10 mL) to affordN-(1-(1H-indol-3-yl)-5-methylhexan-2-yl)-2-(4-methylpiperazin-1-yl)thiazole-5-carboxamide(0.175 g, 60%) as a white solid. HPLC Purity: 99.8%. MS (ESI) m/e[M+H]⁺/RT (min)/%: 440.00/2.25/99.7%. ¹H NMR (400 MHz, DMSO-d₆) δ 0.80(d, J=6.0 Hz, 6H), 1.26-1.15 (m, 2H), 1.57-1.40 (m, 3H), 2.22 (s, 3H),2.40-2.48 (m, 4H), 2.94-2.77 (m, 2H), 3.42-3.42 (m, 4H), 4.02-4.16 (m,1H), 6.95 (t, J=7.4 Hz, 1H), 7.04 (t, J=7.4 Hz, 1H), 7.12 (s, 1H), 7.31(d, J=8.0 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.80 (s, 1H), 7.94 (d, J=8.6Hz, 1H), 10.75 (s, 1H).

Example 15:N-(1-Cyclopentyl-2-(1H-indol-3-yl)ethyl)-2-(4-methylpiperazin-1-yl)thiazole-5-carboxamide

Step 1. Synthesis of 1-cyclopentyl-2-(1H-indol-3-yl)ethan-1-one

To a solution of 3-methylindole (0.20 g, 1.52 mmol) in dichloroethane (3mL) was added AlCl₃ (0.95 g, 4.50 mmol) at 0° C. The reaction mixturewas stirred at room temperature for 30 min. The reaction mixture wascooled to 0° C. followed by dropwise addition of cyclopentanecarbonylchloride (0.27 g, 2.00 mmol). The reaction mixture was stirred at roomtemperature for 16 h. The reaction mixture was quenched with ice andextracted with DCM (3×25 mL). The organic layer was separated, driedover anhydrous Na₂SO₄ and concentrated in vacuo. The crude obtained waspurified by column chromatography (silica 100-200 mesh, 1 to 10% EtOAcin hexanes) to afford 1-cyclopentyl-2-(1H-indol-3-yl)ethan-1-one (0.17g, 50%) as a brown liquid. MS (ESI) m/e [M+H]⁺/RT (min)/%:228.00/3.4/89.9%. ¹H NMR (400 MHz, DMSO-d6) δ 1.44-1.80 (m, 8H),3.08-2.99 (m, 1H), 3.84 (s, 2H), 6.97 (t, J=7.0 Hz, 1H), 7.06 (t, J=7.0Hz, 1H), 7.22 (s, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H),10.92 (s, 1H).

Step 2. Synthesis of 1-cyclopentyl-2-(1H-indol-3-yl) ethan-1-aminehydrochloride

To a solution of 1-cyclopentyl-2-(1H-indol-3-yl)ethan-1-one (0.17 g,0.74 mmol) in MeOH (10 mL) was added NH₄OAc (0.49 g, 5.76 mmol), and thereaction mixture was stirred at 50° C. for 10 min. NaBH₃CN (0.06 g, 0.96mmol) was added portion-wise, and the reaction mixture was heated toreflux for 16 h. The reaction mixture was quenched with 3 N HCl (10 mL)and filtered. The crude obtained was washed with hexanes (10 mL) anddried in vacuo to afford 1-cyclopentyl-2-(1H-indol-3-yl) ethan-1-aminehydrochloride (0.13 g, 77%) as an off-white solid. MS (ESI) m/e[M+H]⁺/RT (min)/%: 229.00/3.7/84.0%. ¹H NMR (400 MHz, DMSO-d₆) δ1.24-1.82 (m, 8H), 1.98-2.06 (m, 1H), 3.09-2.92 (m, 2H), 3.34-3.28 (m,1H), 6.94 (t, J=7.0 Hz, 1H), 7.01 (t, J=7.2 Hz, 1H), 7.28 (s, 1H), 7.36d, J=7.6 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.81 (s, 2H), 11.03 (s, 1H).

Step 3. Synthesis of2-bromo-N-(1-cyclopentyl-2-(1H-indol-3-yl)ethyl)thiazole-5-carboxamide

To a solution of 1-cyclopentyl-2-(1H-indol-3-yl) ethan-1-aminehydrochloride (0.40 g, 2.43 mmol) and 2-bromothiazole-5-carboxylic acid(0.60 g, 2.91 mmol) in DMF (20 mL) was added Mukaiyama reagent (1.05 g,4.13 mmol) followed by addition of DIPEA (1.56 g, 12.1 mmol). Thereaction mixture was stirred at room temperature for 6 h. The reactionmixture was diluted with H₂O (100 mL) and extracted with DCM (3×25 mL).The organic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The crude obtained was purified by columnchromatography (silica 100-200 mesh, 1 to 10% MeOH in DCM) andtriturated with Et₂O (5 mL) and pentane (5 mL) to afford2-bromo-N-(1-cyclopentyl-2-(1H-indol-3-yl)ethyl)thiazole-5-carboxamide(0.155 g, 15%) as an off-white solid. MS (ESI) m/e [M+H]⁺/RT (min)/%:419.65/3.6/78.1%. ¹H NMR (400 MHz, DMSO-d₆) δ 1.20-1.80 (m, 8H),2.02-2.12 (m, 1H), 2.80-3.01 (m, 2H), 4.02-4.14 (m, 1H), 7.01 (t, J=7.2Hz, 1H), 6.94 (t, J=7.0 Hz, 1H), 7.12 (s, 1H), 7.29 (d, J=7.7 Hz, 1H),7.51 (d, J=7.8 Hz, 1H), 8.19 (s, 1H), 8.44 (d, J=8.6 Hz, 1H), 10.72 (s,1H).

Step 4

To a solution of2-bromo-N-(1-cyclopentyl-2-(1H-indol-3-yl)ethyl)thiazole-5-carboxamide(0.15 g, 0.35 mmol) and 1-methylpiperazine (0.04 g, 0.43 mmol) in CH₃CN(3 mL) was added K₂CO₃ (0.15 g, 1.07 mmol) and the reaction mixture washeated at 80° C. for 16 h. The reaction mixture was concentrated invacuo. The residue was diluted with H₂O (10 mL) and extracted with 10%MeOH in DCM (3×10 mL). The organic layer was separated, dried overanhydrous Na₂SO₄ and concentrated in vacuo. The crude obtained waspurified by column chromatography (silica 230-400 mesh, 2 to 4% MeOH inDCM) and dissolved in DCM (1 drop) and reprecipitated with pentane (10mL) to affordN-(1-cyclopentyl-2-(1H-indol-3-yl)ethyl)-2-(4-methylpiperazin-1-yl)thiazole-5-carboxamide(0.07 g, 44%) as a white solid. HPLC Purity: 97.3%. MS (ESI) m/e[M+H]⁺/RT (min)/%: 438.00/2.71/98.4%. ¹H NMR (400 MHz, DMSO-d₆) δ1.21-1.82 (m, 8H), 2.08-1.99 (m, 1H), 2.21 (s, 3H), 2.36-2.44 (m, 4H),2.83-3.01 (m, 2H), 3.40-3.48 (m, 4H), 4.02-4.14 (m, 1H), 6.94 (t, J=7.4Hz, 1H), 7.04 (t, J=7.4 Hz, 1H), 7.12 (s, 1H), 7.29 (d, J=8.1 Hz, 1H),7.51 (d, J=7.8 Hz, 1H), 7.79 (s, 1H), 7.89 (d, J=8.8 Hz, 1H), 10.71 (s,1H).

Example 16:N-(2-(1H-Indol-3-yl)ethyl)-N-butyl-2-(4-methylpiperazin-1-yl)thiazole-5-carboxamide

Step 1: Synthesis of 2-(1H-indol-3-yl)acetaldehyde

To a solution of 2-(1H-indol-3-yl)ethan-1-ol (1.00 g, 6.20 mmol) inCH₃CN (25 mL) was added 2-iodoxybenzoic acid (0.52 g, 18.0 mmol). Thereaction mixture was heated at 80° C. for 3 h. The reaction mixture wasfiltered through a pad of diatomaceous earth, washing with CH₃CN (10mL). The filtrate was concentrated in vacuo to afford 2-(1H-indol-3-yl)acetaldehyde (0.90 g, 91%) as a brown semi solid. This compound was usedas such for the next reaction without further purification.

Step 2: Synthesis of N-(2-(1H-indol-3-yl)ethyl)butan-1-amine

To a solution of 2-(1H-indol-3-yl)acetaldehyde (0.90 g, 5.60 mmol) inMeOH (20 mL) was added nBuNH₂ (0.83 g, 11.0 mmol), and the reactionmixture was stirred at room temperature for 10 min. NaBH₃CN (0.70 g,11.0 mmol) was added portion wise, and the reaction mixture was heatedat reflux for 16 h. The reaction mixture was diluted with 3 N HCl (10mL) and decanted. The crude product obtained was purified by trituratingwith hexanes (10 mL) and Et₂O (10 mL) to affordN-(2-(1H-indol-3-yl)ethyl)butan-1-amine (0.59 g, 48%) as an off-whitesolid. MS (ESI) m/e [M+]⁺/RT (min)/%: 216.00/2.77/44.5%. ¹H NMR (400MHz, DMSO-d₆) δ 0.86 (t, J=7.2 Hz, 3H), 1.22-1.42 (m, 4H), 1.80 (brs,1H), 2.55 (t, J=6.9 Hz, 2H), 2.76-2.84 (m, 4H), 6.96 (t, J=7.4 Hz, 1H),7.05 (t, J=7.4 Hz, 1H), 7.12 (d, J=2.0 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H),7.50 (d, J=7.8 Hz, 1H), 10.77 (s, 1H).

Step 3: Synthesis ofN-(2-(1H-indol-3-yl)ethyl)-2-bromo-N-butylthiazole-5-carboxamide

To a solution of N-(2-(1H-indol-3-yl)ethyl)butan-1-amine (0.50 g, 2.31mmol) and 2-bromothiazole-5-carboxylic acid (0.58 g, 2.77 mmol) in DMF(30 mL) was added Mukaiyama reagent (1.00 g, 3.93 mmol) followed byN,N-diisopropylethylamine (0.89 g, 6.94 mmol). The reaction mixture wasstirred at room temperature for 16 h. The reaction mixture was dilutedwith H₂O (100 mL) and extracted with DCM (3×50 mL). The organic layerwas separated, washed with brine (50 mL), dried over anhydrous Na₂SO₄and concentrated in vacuo. The crude obtained was purified by columnchromatography (silica 230-400 mesh, 1 to 10% MeOH in DCM) andtriturating with Et₂O (10 mL) and pentane (10 mL) to affordN-(2-(1H-indol-3-yl)ethyl)-2-bromo-N-butylthiazole-5-carboxamide (0.60g, 64%) as an off-white solid. MS (ESI) m/e [M+H+1]⁺/RT (min)/%:407.6/3.58/97.0%.

Step 4

To a solution ofN-(2-(1H-indol-3-yl)ethyl)-2-bromo-N-butylthiazole-5-carboxamide (0.20g, 0.49 mmol) and N-methylpiperazine (0.07 g, 0.73 mmol) in CH₃CN (4 mL)was added K₂CO₃ (0.20 g, 1.47 mmol), and the reaction mixture was heatedat 80° C. for 16 h. The reaction mixture was concentrated in vacuo. Theresidue was diluted with H₂O (20 mL) and extracted with 10% MeOH in DCM(3×20 mL). The organic layer was separated, dried over anhydrous Na₂SO₄and concentrated in vacuo. The crude obtained was purified by columnchromatography (silica 230-400 mesh, 0.5 to 3.5% MeOH in DCM) andtriturated with pentane (10 mL) to affordN-(2-(1H-indol-3-yl)ethyl)-N-butyl-2-(4-methylpiperazin-1-yl)thiazole-5-carboxamide(0.08 g, 38%) as an off-white solid. HPLC Purity: 99.6%. MS (ESI) m/e[M+H]⁺/RT (min)/%: 426.00/2.66/99.2%. ¹H NMR (400 MHz, DMSO-d₆) δ 0.88(t, J=7.3 Hz, 3H), 1.28 (m, 2H), 1.55 (m, 2H), 2.22 (s, 3H), 2.44-2.36(m, 4H), 3.02-2.94 (m, 2H), 3.48-3.40 (m, 6H), 3.64-3.76 (m, 2H), 6.97(t, J=7.4 Hz, 1H), 7.06 (t, J=7.5 Hz, 1H), 7.18 (d, J=1.9 Hz, 1H), 7.33(d, J=8.1 Hz, 1H), 7.44 (s, 1H), 7.53 (d, J=7.7 Hz, 1H), 10.85 (s, 1H).

Example 17:N-(1-(1H-Indol-3-yl)hexan-2-yl)-2-(3-(difluoromethyl)-4-methylpiperazin-1-yl)thiazole-5-carboxamide

Step 1: Synthesis of 1-(tert-butyl) 3-methyl4-methylpiperazine-1,3-dicarboxylate

To a solution of KOH (24.0 g, 422 mmol) in H₂O (80 mL) was added Et₂O(200 mL) at 0° C. followed by addition of N-nitroso-N-methylurea (12.0g, 116 mmol) portion-wise at 0° C. The reaction mixture was stirred atsame temperature for 10 min. The separated Et₂O layer was added to asolution of 4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (4.00 g,17.3 mmol) in Et₂O (200 mL) at 0° C. The reaction mixture was stirred atroom temperature for 16 h. The reaction mixture was quenched with iceH₂O (25 mL) and extracted with Et₂O (3×50 mL). The organic layer wasseparated, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Thecrude obtained was purified by column chromatography (silica 100-200mesh, 5 to 40% EtOAc in hexanes) to afford 1-(tert-butyl) 3-methyl4-methylpiperazine-1,3-dicarboxylate (2.50 g, 45%) as a yellow liquid.¹H NMR (400 MHz, DMSO-d₆) δ 1.40 (s, 9H), 2.25 (s, 3H), 2.84-2.96 (m,2H), 3.00-3.10 (m, 1H), 3.34-3.40 (m, 1H), 3.42-3.52 (m, 2H), 3.63 (s,3H), 4.02-4.16 (m, 1H).

Step 2: Synthesis of tert-butyl3-formyl-4-methylpiperazine-1-carboxylate

To a solution of 1-(tert-butyl) 3-methyl4-methylpiperazine-1,3-dicarboxylate (1.30 g, 5.03 mmol) in toluene (25mL) was added diisobutylaluminum hydride (12.6 mL, 12.6 mmol) dropwiseover 30 min at −78° C. The reaction mixture was stirred at sametemperature for 1 h. The reaction mixture was quenched with saturatedNH₄Cl (15 mL) and extracted with 10% MeOH in DCM (3×30 mL). The organiclayer was separated, dried over anhydrous sodium sulphate andconcentrated in vacuo. The crude obtained was purified by columnchromatography (basic alumina, 0.5% to 1% MeOH in DCM) to affordtert-butyl 3-formyl-4-methylpiperazine-1-carboxylate (0.68 g, 60%) as abrown liquid. ¹H NMR (400 MHz, Chloroform-d) δ 1.46 (s, 9H), 2.37 (s,3H), 3.01-2.85 (m, 4H), 3.14-3.03 (m, 1H), 3.52-3.40 (m, 1H), 3.84-3.92(m, 1H), 9.61 (s, 1H).

Step 3: Synthesis of tert-butyl3-(difluoromethyl)-4-methylpiperazine-1-carboxylate

To a solution of diethylaminosulfur trifluoride (1.14 g, 7.12 mmol) inDCM (20 mL) was added tert-butyl3-formyl-4-methylpiperazine-1-carboxylate (0.65 g, 2.85 mmol) solutionin DCM (20 mL) at −78° C. The reaction mixture was stirred at −78° C.for 1 h and at room temperature for 16 h. The reaction mixture waspoured in to saturated NaHCO₃ (20 mL) solution and extracted with DCM(3×25 mL). The organic layer was separated, dried over anhydrous Na₂SO₄and concentrated in vacuo. The crude obtained was purified by columnchromatography (basic alumina, 1 to 2% MeOH in DCM) to afford tert-butyl3-(difluoromethyl)-4-methylpiperazine-1-carboxylate (0.35 g, 49%) as abrown liquid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.39 (s, 9H), 2.32 (s, 3H),3.01-2.85 (m, 4H), 3.14-3.03 (m, 1H), 3.52-3.40 (m, 1H), 3.76-3.84 (m,1H), 6.30 (t, J=54.0 Hz, 1H).

Step 4: Synthesis of 2-(difluoromethyl)-1-methylpiperazine

To a solution of tert-butyl3-(difluoromethyl)-4-methylpiperazine-1-carboxylate (0.35 g, 1.40 mmol)in dioxane (10 mL) was added 4 M HCl in dioxane (20 mL) at 0° C. Thereaction mixture was stirred at room temperature for 30 min. Thereaction mixture was concentrated in vacuo. The crude obtained waspurified by triturating with pentane (2×10 mL) at 0° C. to afford2-(difluoromethyl)-1-methylpiperazine (0.20 g, 76%) as a brown solid.

Step 5

To a solution ofN-(1-(1H-indol-3-yl)hexan-2-yl)-2-bromothiazole-5-carboxamide (0.20 g,0.49 mmol) and 2-(difluoromethyl)-1-methylpiperazine (0.10 g, 0.58 mmol)in CH₃CN (4 mL) was added K₂CO₃ (0.27 g, 1.96 mmol) followed by additionof tetrabutylammonium bromide (0.002 g, 0.05 mmol). The reaction mixturewas heated in sealed tube at 80° C. for 48 h. The reaction mixture wasconcentrated in vacuo. The residue was diluted with H₂O (5 mL) andextracted with DCM (3×10 mL). The organic layer was separated, driedover anhydrous Na₂SO₄ and concentrated in vacuo. The crude obtained waspurified by preparative HPLC to affordN-(1-(1H-indol-3-yl)hexan-2-yl)-2-(3-(difluoromethyl)-4-methylpiperazin-1-yl)thiazole-5-carboxamide(0.05 g, 23%) as a white solid. HPLC Purity: 96.6%. MS (ESI) m/e[M+H]⁺/RT (min)/%: 476.00/2.58/98.8%. ¹H NMR (400 MHz, DMSO-d₆) δ 0.82(t, J=7.3 Hz, 3H), 1.16-1.60 (m, 6H), 2.37 (s, 3H), 2.60-2.72 (m, 2H),2.80-2.96 (m, 3H), 3.20-3.38 (m, 2H), 3.60-3.50 (m, 1H), 3.83 (d, J=12.4Hz, 1H), 4.08-4.20 (m, 1H), 6.30 (t, J=54.0 Hz, 1H), 7.03-6.94 (m, 2H),7.09 (s, 1H), 7.30 (d, J=7.8 Hz, 1H), 7.56 (d, J=7.3 Hz, 1H), 7.81 (s,1H), 7.97 (d, J=7.8 Hz, 1H), 10.75 (s, 1H).

Example 18:N-(1-(1H-Indol-3-yl)hexan-2-yl)-2-(3-(fluoromethyl)-4-methylpiperazin-1-yl)thiazole-5-carboxamide

Step 1: Synthesis of tert-butyl3-(fluoromethyl)-4-methylpiperazine-1-carboxylate

To a solution of tert-butyl3-(hydroxymethyl)-4-methylpiperazine-1-carboxylate (0.70 g, 3.00 mmol)in DCM (25 mL) was added diethylaminosulfur trifluoride (0.59 g, 3.60mmol) dropwise at 0° C. The reaction mixture was heated at 45° C. for 16h. The reaction mixture was quenched with saturated NaHCO₃ (20 mL)solution. The organic layer was separated, washed with brine (20 mL),dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crudeobtained was purified by column chromatography (silica 100-200 mesh,1-10% EtOAc in hexanes) to afford tert-butyl3-(fluoromethyl)-4-methylpiperazine-1-carboxylate (0.50 g, 71%) as awhite solid. This compound was used as such for the next reactionwithout further purification and analysis.

Step 2: Synthesis of 2-(fluoromethyl)-1-methylpiperazine

To a solution of tert-butyl3-(fluoromethyl)-4-methylpiperazine-1-carboxylate (0.50 g, 2.15 mmol) indioxane (10 mL) was added dioxane*HCl (15 mL) at 0° C. and the reactionmixture was stirred at room temperature for 16 h. The reaction mixturewas cooled to 10° C. and filtered. The crude obtained was washed withDCM (10 mL) and dried in vacuo to afford2-(fluoromethyl)-1-methylpiperazine (0.15 g, 38%) as an off-whitesemisolid. MS (ESI) m/e [M+H]⁺/RT (min)/%: 132.90/1.3/73.6%.

Step 3

To a solution of 2-(fluoromethyl)-1-methylpiperazine (0.09 g, 0.53 mmol)and N-(1-(1H-indol-3-yl)hexan-2-yl)-2-bromothiazole-5-carboxamide (0.20g, 0.49 mmol) in CH₃CN (4.5 mL) was added K₂CO₃ (0.20 g, 1.47 mmol) andthe reaction mixture was heated at 80° C. for 16 h. The reaction mixturewas concentrated in vacuo. The residue was diluted with H₂O (10 mL) andextracted with 10% MeOH in DCM (10 mL). The organic layer was separated,dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crudeobtained was purified by column chromatography (silica 230-400 mesh, 0.5to 3.5% MeOH in DCM) and triturating with pentane (10 mL) to affordN-(1-(1H-indol-3-yl)hexan-2-yl)-2-(3-(fluoromethyl)-4-methylpiperazin-1-yl)thiazole-5-carboxamide(0.115 g, 51%) as a yellow solid. HPLC Purity: 98.7%. MS (ESI) m/e[M+H]⁺/RT (min)/%: 458.00/2.76/99.4%. ¹H NMR (400 MHz, DMSO-d₆) δ 0.81(t, J=6.9 Hz, 3H), 1.18-1.50 (m, 6H), 2.30 (s, 3H), 2.32-2.40 (m, 2H),2.75-2.91 (m, 3H), 3.01 (t, J=11.2 Hz, 1H), 3.17 (t, J=11.5 Hz, 1H),3.69 (d, J=12.2 Hz, 1H), 3.85 (d, J=12.2 Hz, 1H), 4.11 (brs, 1H),4.48-4.64 (m, 2H), 6.92-7.00 (m, 1H), 7.04 (t, J=7.1 Hz, 1H), 7.09 (brs,1H), 7.31 (d, J=7.3 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.81 (s, 1H), 7.96(d, J=8.3 Hz, 1H), 10.75 (brs, 1H).

Example 19:N-(1-(1H-Indol-3-yl)hexan-2-yl)-2-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)thiazole-5-carboxamide

Step 1: Synthesis of methyl 5-oxopyrrolidine-2-carboxylate

To a solution of 5-oxopyrrolidine-2-carboxylic acid (9.00 g, 69.7 mmol)in MeOH (20 mL) was added SOCl₂ (6.60 mL, 90.6 mmol) at 0° C. Thereaction mixture was stirred at room temperature for 16 h. The reactionmixture was concentrated in vacuo. The residue was diluted with H₂O (100mL) and extracted with EtOAc (100 mL). The organic layer was separated,washed with H₂O (20 mL) and brine (50 mL), dried over anhydrous Na₂SO₄and concentrated in vacuo to afford methyl5-oxopyrrolidine-2-carboxylate (5.60 g, 58%) as a colorless liquid. Thiscompound was used as such for the next reaction without furtherpurification. MS (ESI) m/e [M+]/RT (min)/%: 144.00/1.33/68.6%. ¹H NMR(400 MHz, DMSO-d₆) δ 2.04-2.18 (m, 2H), 3.56-3.62 (m, 2H), 3.70 (s, 3H),4.16-4.22 (m, 1H), 7.97 (s, 1H).

Step 2: Synthesis of methyl 1-methyl-5-oxopyrrolidine-2-carboxylate

To a solution of methyl 5-oxopyrrolidine-2-carboxylate (4.50 g, 31.4mmol) in 1,2-dimethoxyethane (40 mL) was added H₂O (0.21 mL, 11.0 mmol),triethylamine (0.44 mL, 3.10 mmol) and K₂CO₃ (7.80 g, 50.6 mmol)followed by addition of dimethyl sulfate (7.13 g, 56.6 mmol) at 20° C.The reaction mixture was stirred at room temperature for 16 h. Thereaction mixture was filtered and washed with 1,2-dimethoxyethane (200mL). The filtrate was concentrated in vacuo below 40° C. The crudeobtained was purified by column chromatography (silica 230-400 mesh, 2%MeOH in DCM) to afford methyl 1-methyl-5-oxopyrrolidine-2-carboxylate(3.85 g, 71%) as a colorless liquid. MS (ESI) m/e [M+]⁺/RT (min)/%:158.00/1.49/85.0%. ¹H NMR (400 MHz, DMSO-d₆) δ 2.18-2.38 (m, 4H), 2.49(s, 3H), 3.76 (s, 3H), 4.28-4.20 (m, 1H).

Step 3: Synthesis of methyl 1-methyl-5-thioxopyrrolidine-2-carboxylate

To a solution of methyl 1-methyl-5-oxopyrrolidine-2-carboxylate (3.80 g,24.2 mmol) in THF (40 mL) was added2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide(Lawesson's reagent; 7.30 g, 18.0 mmol). The reaction mixture wasstirred at room temperature for 16 h. The reaction mixture was quenchedwith saturated NaHCO₃ (100 mL) and extracted with EtOAc (2×100 mL). Theorganic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated in vacuo below 40° C. The crude obtained was purified bycolumn chromatography (silica 100-200 mesh, 1% MeOH in DCM) to affordmethyl 1-methyl-5-thioxopyrrolidine-2-carboxylate (2.55 g, 61%) as ayellow solid. MS (ESI) m/e [M+H+1]⁺/RT (min)/%: 174.00/2.01/99.9%. ¹HNMR (400 MHz, DMSO-d₆) δ 2.00-2.12 (m, 1H), 2.45-2.32 (m, 1H), 2.82-2.96(m, 2H), 3.14 (s, 3H), 3.76 (s, 3H), 4.75 (d, J=7.7 Hz, 1H).

Step 4: Synthesis of5-mesityl-2-(methoxycarbonyl)-1-methyl-3,4-dihydro-2H-pyrrol-1-iumiodide

To a solution of methyl 1-methyl-5-thioxopyrrolidine-2-carboxylate (2.50g, 14.4 mmol) in toluene (10 mL) was added CH₃I (15 mL). The reactionmixture was stirred at room temperature for 16 h. The reaction mixturewas concentrated in vacuo. The crude obtained was purified bytriturating with toluene (10 mL) and pentane (10 mL) to afford5-mesityl-2-(methoxycarbonyl)-1-methyl-3,4-dihydro-2H-pyrrol-1-iumiodide (3.20 g crude) as yellow semi solid. ¹H NMR (400 MHz, DMSO-d₆) δ2.32-2.40 (m, 1H), 2.44 (s, 3H), 2.58-2.64 (m, 1H), 2.89 (s, 3H),3.51-3.60 (m, 2H), 3.77 (s, 3H), 5.23 (d, J=7.6 Hz, 1H).

Step 5: Synthesis of methyl (E)-1-methyl-5-(nitromethylene)pyrrolidine-2-carboxylate

To a solution of5-mesityl-2-(methoxycarbonyl)-1-methyl-3,4-dihydro-2H-pyrrol-1-iumiodide (3.18 g, 15.9 mmol) in DMF (30 mL) was added triethylamine (2.40mL, 17.5 mmol) followed by dropwise addition of CH₃NO₂ (6.37 mL, 118mmol). The reaction mixture was stirred at room temperature for 16 h.The reaction mixture was concentrated in vacuo. The crude obtained waspurified by column chromatography (silica 100-200 mesh, 1% MeOH in DCM)to afford methyl(E)-1-methyl-5-(nitromethylene)pyrrolidine-2-carboxylate (0.70 g, 21%)as a light yellow solid. MS (ESI) m/e [M+H+1]⁺/RT (min)/%:200.8/1.97/97.6%. ¹H NMR (400 MHz, Chloroform-d) δ 2.18-2.26 (m, 1H),2.36-2.44 (m, 1H), 2.89 (s, 3H), 3.28-3.40 (m, 1H), 3.68-3.56 (m, 1H),3.79 (s, 3H), 4.33-4.26 (m, 1H), 6.72 (s, 1H).

Step 6: Synthesis of 8-methyl-3,8-diazabicyclo[3.2.1]octan-2-one

To a solution of methyl(E)-1-methyl-5-(nitromethylene)pyrrolidine-2-carboxylate (0.70 g, 3.50mmol) in MeOH (30 mL) was added Pd/C (0.70 g). The reaction mixture wasstirred at room temperature under hydrogen pressure for 24 h. Thereaction mixture was filtered through a pad of diatomaceous earth,washing with MeOH (10 mL). The filtrate was concentrated in vacuo toafford 8-methyl-3,8-diazabicyclo[3.2.1]octan-2-one (0.35 g crude) as ayellow liquid. This compound was used as such for the next reactionwithout further purification. MS (ESI) m/e [M+H+1]⁺/RT (min)/%:141.00/1.19/84.6%. ¹H NMR (400 MHz, Chloroform-d) 1.69-1.86 (m, 2H),2.16-2.24 (m, 2H), 2.49 (s, 3H), 2.97 (d, J=11.3 Hz, 1H), 3.32-3.40 (m,2H), 3.74-3.63 (m, 1H), 5.63 (s, 1H).

Step 7: Synthesis of 8-methyl-3,8-diazabicyclo[3.2.1]octane

To a solution of 8-methyl-3,8-diazabicyclo[3.2.1]octan-2-one (0.35 g,2.50 mmol) in THF (4 mL) was added 1 M lithium aluminum hydride solutionin THF (4 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hand then heated at 50° C. for 6 h. The reaction mixture was quenchedwith aqueous potassium sodium tartrate (4 mL) solution and filtered. Thecrude obtained washed with THF (4 mL) to afford8-methyl-3,8-diazabicyclo[3.2.1]octane (0.18 g crude) as yellow liquid.MS (ESI) m/e [M+H+1]⁺/RT (min)/%: 407.6/3.58/97.0%. ¹H NMR (400 MHz,Chloroform-d) δ 1.74-1.63 (m, 4H), 2.24 (s, 3H), 2.60-2.64 (m, 2H),2.98-3.04 (m, 4H).

Step 8

To a solution ofN-(1-(1H-indol-3-yl)hexan-2-yl)-2-bromothiazole-5-carboxamide (0.20 g,0.49 mmol) and 8-methyl-3,8-diazabicyclo[3.2.1]octane (0.07 g, 0.58mmol) in CH₃CN (4 mL) was added K₂CO₃ (0.20 g, 1.47 mmol) and thereaction mixture was heated at 100° C. for 16 h. The reaction mixturewas concentrated in vacuo. The residue was diluted with H₂O (10 mL) andextracted with DCM (3×10 mL). The organic layer was separated, driedover anhydrous Na₂SO₄ and concentrated in vacuo. The crude obtained waspurified by column chromatography (silica 230-400 mesh, 0.5 to 3% MeOHin DCM) and triturating with pentane (10 mL) to affordN-(1-(1H-indol-3-yl)hexan-2-yl)-2-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)thiazole-5-carboxamide(0.10 g, 45%) as an off-white solid. HPLC Purity: 99.0%. MS (ESI) m/e[M+H]⁺/RT (min)/%: 452.00/2.62/99.0%. ¹H NMR (400 MHz, DMSO-d₆) δ 0.82(t, J=7.3 Hz, 3H), 1.16-1.40 (m, 4H), 1.42-1.60 (m, 4H), 1.92-1.98 (m,2H), 2.23 (s, 3H), 2.80-2.92 (m, 2H), 3.12-3.22 (m, 4H), 3.46 (d, J=11.0Hz, 2H), 4.06-4.16 (m, 1H), 6.96-7.04 (m, 2H), 7.11 (s, 1H), 7.31 (d,J=7.7 Hz, 1H), 7.57 (d, J=7.5 Hz, 1H), 7.79 (s, 1H), 7.90 (d, J=8.2 Hz,1H), 10.74 (s, 1H).

Example 20:N-(2-(1H-Indol-3-yl)-1-phenylethyl)-2-(4-methylpiperazin-1-yl)thiazole-5-carboxamide

Step 1: Synthesis of 2-(1H-indol-3-yl)-N-methoxy-N-methylacetamide

To a solution of 2-(1H-indol-3-yl)acetic acid (9.00 g, 51.4 mmol) andN-methylmorpholine (5.19 g, 51.4 mmol) in THF (90 mL) was addedisopropylchloroformate (56.4 mL, 56.5 mmol) solution in toluene dropwise at −20° C. and stirred at same temperature for 30 min. A suspensionof N,O-dimethylhydroxylamine hydrochloride (7.38 g, 77.1 mmol) andtriethylamine (6.00 g, 61.7 mmol) in DMF (5 mL) was added at 0° C., andthe reaction mixture was stirred at 0° C. for 1 h. The reaction mixturewas quenched with H₂O (20 mL) and extracted with EtOAc (2×150 mL). Theorganic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The crude obtained was purified by columnchromatography (silica 100-200 mesh, 1 to 2% MeOH in DCM) to afford2-(1H-indol-3-yl)-N-methoxy-N-methylacetamide (8.00 g, 64%) as a brownsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 3.11 (s, 3H), 3.32 (s, 3H), 3.79 (s,2H), 6.96 (t, J=7.1 Hz, 1H), 7.06 (t, J=7.1 Hz, 1H), 7.34 (d, J=8.1 Hz,1H), 7.51 (d, J=7.9 Hz, 1H), 7.95 (s, 1H), 10.88 (s, 1H).

Step 2: Synthesis ofN-methoxy-N-methyl-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indol-3-yl)acetamide

To a solution of 2-(1H-indol-3-yl)-N-methoxy-N-methylacetamide (8.00 g,36.8 mmol) in DCM (50 mL) was added 3,4-dihydro-2H-pyran (3.71 g, 44.2mmol) at 0° C., and the reaction mixture was stirred at same temperaturefor 15 min. p-Toluenesulfonic acid (0.63 g, 3.68 mmol) was added, andthe reaction mixture was stirred at room temperature for 16 h. Thereaction mixture was extracted with DCM (3×20 mL). The organic layer wasseparated, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Thecrude obtained was purified by column chromatography (silica 100-200mesh, 0.5 to 2% MeOH in DCM) to affordN-methoxy-N-methyl-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indol-3-yl)acetamide (6.00 g, 54%) as a brown solid. ¹H NMR (400 MHz, Chloroform-d)δ 1.40-2.20 (m, 6H), 3.21 (s, 3H), 3.50-3.58 (m, 1H), 3.74 (t, J=10.8Hz, 1H), 3.90 (s, 3H), 4.10 (s, 2H), 5.48 (d, J=9.9 Hz, 1H), 7.10-7.30(m, 2H), 7.33 (s, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.64 (d, J=7.5 Hz, 1H).

Step 3: Synthesis of1-phenyl-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indol-3-yl)ethan-1-one

To a solution ofN-methoxy-N-methyl-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indol-3-yl)acetamide(6.00 g, 19.8 mmol) in THF (60 mL) was added PhMgBr (4.80 g, 39.6 mmol)dropwise at 0° C. The reaction mixture was stirred at room temperaturefor 16 h. The reaction mixture was quenched with saturated NH₄Cl (30 mL)and extracted with EtOAc (3×150 mL). The organic layer was separated,dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crudeobtained was purified by column chromatography (silica 100-200 mesh, 0to 3% MeOH in DCM) to afford1-phenyl-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indol-3-yl)ethan-1-one (5.00g, 79%) as a light yellow liquid. ¹H NMR (400 MHz, Chloroform-d) δ1.66-2.20 (m, 6H), 3.73 (t, J=10.8 Hz, 1H), 4.09 (d, J=11.0 Hz, 1H),4.39 (s, 2H), 5.46 (d, J=9.9 Hz, 1H), 6.84 (d, J=7.3 Hz, 1H), 7.20-7.30(m, 3H), 7.36-7.47 (m, 4H), 7.57 (dd, J=25.4, 7.1 Hz, 1H), 8.06 (d,J=7.2 Hz, 1H).

Step 4: Synthesis of1-phenyl-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indol-3-yl)ethan-1-amine

To a solution of1-phenyl-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indol-3-yl)ethan-1-one (1.00g, 3.13 mmol) in MeOH (10 mL) was added NH₄OAc (1.96 g, 31.3 mmol) andthe reaction mixture was stirred at 0° C. for 10 min. NaBH₃CN (0.06 g,0.96 mmol) was added portion-wise and the reaction mixture was heated at60° C. for 5 h. The reaction mixture was quenched with H₂O (10 mL) andextracted with 10% MeOH in DCM. The organic layer was separated, driedover anhydrous Na₂SO₄ and concentrated in vacuo. The crude obtained waspurified by column chromatography (silica 100-200 mesh, 1 to 3% MeOH inDCM) to afford1-phenyl-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indol-3-yl)ethan-1-amine(0.60 g, 60%) as a brown liquid. MS (ESI) m/e [M+H+1]⁺/RT (min)/%:321.00/3.3/59.1%.

Step 5: Synthesis of2-bromo-N-(1-phenyl-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indol-3-yl)ethyl)thiazole-5-carboxamide

To a solution of1-phenyl-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indol-3-yl)ethan-1-amine(0.60 g, 1.87 mmol) and 2-bromothiazole-5-carboxylic acid (0.43 g, 2.06mmol) in CH₃CN (8 mL) was added pyridine (0.44 g, 5.62 mmol) followed byaddition ofN-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (HATU; 0.71 g, 1.87 mmol). The reactionmixture was heated at 80° C. for 16 h. The reaction mixture wasconcentrated in vacuo. The crude obtained was purified by columnchromatography (silica 100-200 mesh, 2 to 3% MeOH in DCM) andtriturating with pentane (2×5 mL) to afford2-bromo-N-(1-phenyl-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indol-3-yl)ethyl)thiazole-5-carboxamide(0.40 g, 42%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ1.44-1.60 (m, 2H), 1.68-1.84 (m, 2H), 1.86-1.98 (m, 2H), 3.14-3.22 (m,2H), 3.62-3.74 (m, 1H), 3.80-3.94 (m, 1H), 5.20-5.28 (m, 1H), 5.52 (d,J=9.0 Hz, 1H), 7.00-7.22 (m, 2H), 7.36-7.23 (m, 4H), 7.44 (d, J=8.2 Hz,3H), 7.63 (d, J=6.9 Hz, 1H), 8.28 (d, J=5.4 Hz, 1H), 9.12 (d, J=7.3 Hz,1H).

Step 6: Synthesis of2-(4-methylpiperazin-1-yl)-N-(1-phenyl-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indol-3-yl)ethyl)thiazole-5-carboxamide

To a solution of2-bromo-N-(1-phenyl-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indol-3-yl)ethyl)thiazole-5-carboxamide(0.39 g, 0.76 mmol) and N-methylpiperazine (0.09 g, 0.91 mmol) in CH₃CN(5 mL) was added K₂CO₃ (0.26 g, 1.90 mmol), and the reaction mixture washeated in a sealed tube at 80° C. for 16 h. The reaction mixture wasconcentrated in vacuo. The residue was diluted with H₂O (10 mL) andextracted with 10% MeOH in DCM (3×20 mL). The organic layer wasseparated, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Thecrude obtained was purified by column chromatography (silica 100-200mesh, 2 to 10% MeOH in DCM) and triturating with pentane (2×5 mL) toafford2-(4-methylpiperazin-1-yl)-N-(1-phenyl-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indol-3-yl)ethyl)thiazole-5-carboxamide(0.30 g, 72%) as an off-white solid. MS (ESI) m/e [M+H+1]⁺/RT (min)/%:530.00/3.21/98.1%. ¹H NMR (400 MHz, DMSO-d₆) δ 1.50-1.98 (m, 6H), 2.19(s, 3H), 2.34-2.40 (m, 4H), 3.10-3.20 (m, 2H), 3.40-3.44 (m, 4H),3.64-3.74 (m, 1H), 3.84-3.94 (m, 1H), 5.16-5.24 (m, 1H), 5.53 (d, J=9.4Hz, 1H), 5.74 (s, 1H), 7.14-7.01 (m, 2H), 7.24-7.31 (m, 3H), 7.38-7.50(m, 3H), 7.62 (s, 1H), 7.89 (s, 1H), 8.56 (s, 1H).

Step 7

To a solution of2-(4-methylpiperazin-1-yl)-N-(1-phenyl-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indol-3-yl)ethyl)thiazole-5-carboxamide(0.25 g, 0.47 mmol) in MeOH (2.5 mL) and H₂O (2.5 mL) was addedconcentrated HCl (0.25 mL) at 0° C., and the reaction mixture was heatedat 50° C. for 2 h. The reaction mixture was concentrated in vacuo. Theresidue was diluted with saturated NaHCO₃ (10 mL) solution and extractedwith 10% MeOH in DCM (3×10 mL). The organic layer was separated, driedover anhydrous Na₂SO₄ and concentrated in vacuo. The crude obtained waspurified by column chromatography (silica 100-200 mesh, 2 to 4% MeOH inDCM) and triturating with pentane (3×2.5 mL) to affordN-(2-(1H-indol-3-yl)-1-phenylethyl)-2-(4-methylpiperazin-1-yl)thiazole-5-carboxamide(0.10 g, 63%) as an off-white solid. HPLC Purity: 99.6%. MS (ESI) m/e[M+H]⁺/RT (min)/%: 446.00/2.56/99.0%. ¹H NMR (400 MHz, DMSO-d₆) δ 2.19(s, 3H), 2.37-2.44 (m, 4H), 3.26-3.09 (m, 2H), 3.40-3.48 (m, 4H),5.19-5.25 (m, 1H), 6.92-7.09 (m, 3H), 7.23 (d, J=6.8 Hz, 1H), 7.28-7.38(m, 3H), 7.41 (d, J=6.9 Hz, 2H), 7.60 (d, J=7.4 Hz, 1H), 7.89 (s, 1H),8.56 (d, J=8.0 Hz, 1H), 10.72 (s, 1H).

Example 21.N-(2-(1H-indol-3-yl)ethyl)-N-methyl-2-(4-methylpiperazin-1-yl)thiazole-5-carboxamide

Step 1. Synthesis ofN-(2-(1H-indol-3-yl)ethyl)-2-bromo-N-methylthiazole-5-carboxamide

To a solution of N-methyl-tryptamine (0.108 g, 0.47 mmol) and2-bromothiazole-5-carboxylic acid (0.098 g, 0.47 mmol) in DMF (4.3 mL)was added HATU (0.182 g, 0.48 mmol) followed by addition of DIPEA (0.378mL, 2.17 mmol). The reaction mixture was stirred at room temperature for16 h. The reaction mixture was diluted with H₂O (20 mL) and extractedwith DCM (3×20 mL). The organic layer was separated, dried overanhydrous Na₂SO₄ and concentrated in vacuo. The crude material waspurified by column chromatography (silica, 0 to 10% methanol indichloromethane) to giveN-(2-(1H-indol-3-yl)ethyl)-2-bromo-N-methylthiazole-5-carboxamide (0.168g, 98%) and used directly in the next reaction.

Step 2

To a solution ofN-(2-(1H-indol-3-yl)ethyl)-2-bromo-N-methylthiazole-5-carboxamide (0.168g, 0.46 mmol) and 1-methylpiperazine (0.102 mL, 0.92 mmol) in THF (1.8mL) was added of DIPEA (0.161 mL, 0.92 mmol), and the reaction mixturewas heated in a sealed tube at 170° C. for 45 min. The reaction mixturewas concentrated in vacuo. The crude obtained was purified by columnchromatography (silica, 0 to 5% methanol in dichloromethane) to giveN-(2-(1H-indol-3-yl)ethyl)-N-methyl-2-(4-methylpiperazin-1-yl)thiazole-5-carboxamide(0.140 g, 79%) as a light yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 8.09(s, 1H), 7.62 (d, J=6.5 Hz, 1H), 7.42 (s, 1H), 7.36 (d, 1H, J=8.0 Hz),7.19 (t, J=7.5 Hz, 1H), 7.11 (t, J=7.5 Hz, 1H), 7.03 (d, J=1.5 Hz, 1H),3.83 (t, J=7.5 Hz, 2H), 3.54-3.62 (m, 4H), 3.14 (s, 3H), 3.19-3.09 (m,2H), 2.52-2.50 (m, 4H), 2.35 (s, 3H). (ESMS⁺): 384.4, (ESMS⁻): 382.3.

Example 22.N-(1-(1H-indol-3-yl)hexan-2-yl)-2-(4-(2-(trifluoromethoxy)ethyl)piperazin-1-yl)thiazole-5-carboxamide

Step 1. Synthesis of1-(4-benzylpiperazin-1-yl)-2-(trifluoromethoxy)ethan-1-one

To a solution of 2-(trifluoromethoxy)acetic acid (0.50 g, 3.47 mmol) inDMF (10 mL) was added HATU (1.71 g, 4.51 mmol). The reaction mixture wasstirred at room temperature for 1 h followed by addition of1-benzylpiperazine (0.67 g, 3.81 mmol) and TEA (1.70 g, 17.3 mmol). Thereaction mixture was stirred at room temperature for 16 h. The reactionmixture was quenched with H₂O (100 mL) and extracted with Et₂O (2×100mL). The organic layer was separated, washed with H₂O (3×50 mL), driedover anhydrous Na₂SO₄, and concentrated in vacuo. The crude obtained waspurified by column chromatography (silica, 100-200 mesh, 0% to 0.5% MeOHin DCM) to afford1-(4-benzylpiperazin-1-yl)-2-(trifluoromethoxy)ethan-1-one (0.65 g, 62%)as a light yellow solid. MS (ESI) m/e [M+H]⁺/Rt/%: 303.00/2.85/99.5%; 1HNMR (400 MHz, CDCl₃) δ 2.42-2.50 (m, 4H), 3.40-3.44 (m, 2H), 3.53 (s,2H), 3.62-3.68 (m, 2H), 4.57 (s, 2H), 7.24-7.36 (m, 5H).

Step 2. Synthesis of 1-benzyl-4-(2-(trifluoromethoxy)ethyl)piperazine

To a solution of1-(4-benzylpiperazin-1-yl)-2-(trifluoromethoxy)ethan-1-one (0.65 g, 2.15mmol) in THF (7 mL) was added BH₃-DMS (1.02 mL, 10.7 mmol) at rt. Thereaction mixture was heated at reflux for 2 h. The reaction mixture wasconcentrated in vacuo. The residue was diluted with H₂O (50 mL) andextracted with EtOAc (3×75 mL). The organic layer was separated, washedwith brine (50 mL), dried over anhydrous Na₂SO₄, and concentrated invacuo to afford 1-benzyl-4-(2-(trifluoromethoxy)ethyl)piperazine (0.50 gcrude) as a colorless liquid. MS (ESI) m/e [M+H]⁺/Rt/%:288.95/3.32/97.6%; ¹H NMR (400 MHz, CDCl₃) δ 2.40-2.60 (m, 8H), 2.69 (t,J=6.0 Hz, 2H), 3.48 (s, 2H), 4.06 (t, J=6.0 Hz, 2H), 7.22-7.38 (m, 5H).

Step 3. Synthesis of 1-(2-(trifluoromethoxy)ethyl)piperazine

To a solution of 1-benzyl-4-(2-(trifluoromethoxy)ethyl)piperazine (0.25g, 0.86 mmol) in MeOH (5 mL) was added Pd/C (0.05 g) followed byaddition of CH₃COOH (catalytic) at rt. The reaction mixture stirred atroom temperature for 3 h under hydrogen pressure. The reaction mixturewas filtered through diatomaceous earth, washing with 20% MeOH in DCM(100 mL), and the filtrate was concentrated in vacuo to afford1-(2-(trifluoromethoxy)ethyl)piperazine (0.14 g crude) as a light yellowliquid. MS (ESI) m/e [M+H]⁺/Rt/%: 199.00/1.97/88.4%; ¹H NMR (400 MHz,CDCl₃) δ 2.50-2.64 (m, 4H), 2.73 (t, J=5.6 Hz, 2H), 2.98-3.06 (m, 4H),4.10 (t, J=5.7 Hz, 2H).

Step 4

To a solution of 1-(2-(trifluoromethoxy)ethyl)piperazine (0.12 g, 0.46mmol) and N-(1-(1H-indol-3-yl)hexan-2-yl)-2-bromothiazole-5-carboxamide(0.17 g, 0.41 mmol) in DMF (3 mL) was added DIPEA (0.54 g, 4.19 mmol).The reaction mixture was heated in sealed tube at 100° C. for 16 h. Thereaction mixture was diluted with H₂O (50 mL) and extracted with EtOAc(3×50 mL). The combined organic layers were dried over anhydrous Na₂SO₄and concentrated in vacuo. The crude obtained was purified bypreparative HPLC to afford the title compound (0.007 g, 3%) as a yellowsolid. HPLC Purity: 93.5%; MS (ESI) m/e [M+H]⁺/Rt/%: 524.00/2.98/92.8%;¹H NMR (400 MHz, DMSO-d₆) δ 0.82 (t, J=7.3 Hz, 3H), 1.16-1.60 (m, 6H),2.40-2.60 (m, 4H), 2.60-2.72 (m, 2H), 3.30 (s, 2H), 3.60-3.50 (m, 4H),4.08-4.14 (m, 1H), 4.18-4.22 (m, 2H), 6.94-7.04 (m, 2H), 7.06 (s, 1H),7.29 (d, J=7.8 Hz, 1H), 7.56 (d, J=7.3 Hz, 1H), 7.80 (s, 1H), 7.97 (d,J=7.8 Hz, 1H), 10.75 (s, 1H).

Example 23.N-(1-(1H-indol-3-yl)hexan-2-yl)-2-(4-methyl-3-(trifluoromethyl)piperazin-1-yl)thiazole-5-carboxamide

Step 1. Synthesis of 1-benzyl-3-(trifluoromethyl)piperazine

To a solution of 3,3-dibromo-1,1,1-trifluoropropan-2-one (2.00 g, 7.43mmol) in H₂O (5 mL) was added NaOAc (1.20 g, 82.1 mmol) and theresulting mixture was heated at 100° C. for 12 h. The reaction mixturewas extracted with EtOAc (30 mL). The organic layer was separated, driedover anhydrous Na₂SO₄, and concentrated in vacuo. The residue wasdiluted with MeOH (10 mL) and treated with N-benzylethane-1,2-diamine(3.50 mL) and NaCNBH₃ (0.92 g, 14.8 mmol) portion wise. The reactionmixture was heated at 60° C. for 16 h. The reaction mixture wasconcentrated in vacuo. The crude obtained was purified by columnchromatography (silica 100-200 mesh, 0.2 to 2% MeOH in DCM) to afford1-benzyl-3-(trifluoromethyl)piperazine (1.10 g, 80%) as a brown liquid.MS (ESI) m/e [M+H]⁺/Rt/%: 245.00/2.86/86.0%; ¹H NMR (400 MHz, DMSO-d₆) δ1.98-2.08 (m, 1H), 2.60-2.86 (m, 6H), 3.50 (s, 2H), 7.20-7.44 (m, 5H).

Step 2. Synthesis of 4-benzyl-1-methyl-2-(trifluoromethyl)piperazine

To a solution of 1-benzyl-3-(trifluoromethyl)piperazine (1.10 g, 4.50mmol) in DCM (20 mL) was added HCHO (0.33 g, 11.2 mmol) dropwise at roomtemperature. The resulting mixture was stirred for 15 min, then wascooled to 0° C. and treated portionwise with Na(OAc)₃BH (2.38 g, 11.2mmol). The reaction mixture was stirred at room temperature for 16 h.The reaction mixture was diluted with H₂O (10 mL) and extracted with 10%MeOH in DCM (3×20 mL). The organic layer was separated, dried overanhydrous Na₂SO₄, and concentrated in vacuo to afford4-benzyl-1-methyl-2-(trifluoromethyl)piperazine (0.50 g crude) as anoff-white solid. This compound was used as such for the next reactionwithout further purification. MS (ESI) m/e [M+H]⁺/Rt/%:258.95/3.41/87.6%.

Step 3. Synthesis of 1-methyl-2-(trifluoromethyl)piperazine

To a solution of 4-benzyl-1-methyl-2-(trifluoromethyl)piperazine (0.50g, 2.04 mmol) in MeOH (20 mL) was added Pd/C (0.20 g) and AcOH (0.50mL). The reaction mixture was stirred at room temperature under hydrogenpressure for 16 h. The reaction mixture was filtered throughdiatomaceous earth, washing with MeOH (20 mL), and the filtrate wasconcentrated in vacuo. The crude obtained was purified by trituratingwith pentane (10 mL) to afford 1-methyl-2-(trifluoromethyl)piperazine(0.50 g crude) as a brown liquid. MS (ESI) m/e [M+H]⁺/Rt/%:168.95/1.73/32.7%.

Step 4

To a solution ofN-(1-(1H-indol-3-yl)hexan-2-yl)-2-bromothiazole-5-carboxamide (0.40 g,0.98 mmol) and 1-methyl-2-(trifluoromethyl)piperazine (0.24 g, 1.47mmol) in CH₃CN (8 mL) was added K₂CO₃ (0.54 g, 3.94 mmol) andtetrabutylammonium bromide (0.03 g, 0.09 mmol). The reaction mixture washeated at 80° C. for 48 h. The reaction mixture was concentrated invacuo. The residue was diluted with H₂O (5 mL) and extracted with 5%MeOH in DCM (3×15 mL). The organic layer was separated, dried overanhydrous Na₂SO₄, and concentrated in vacuo. The crude obtained waspurified by preparative HPLC to afford the title compound (0.08 g, 16%)as an off-white solid. HPLC Purity: 99.7%; MS (ESI) m/e [M+H]⁺/Rt/%:494.00/3.02/99.9%; ¹H NMR (400 MHz, DMSO-d₆) δ 0.81 (t, J=6.7 Hz, 3H),1.18-1.33 (m, 4H), 1.47-1.56 (m, 2H), 2.70 (dd, J=12.5, 5.9 Hz, 1H),2.76-2.98 (m, 3H), 3.40-3.50 (m, 4H), 3.38-3.47 (m, 2H), 4.08-4.14 (m,1H), 6.95 (t, J=7.3 Hz, 1H), 7.00-7.12 (m, 2H), 7.31 (d, J=8.0 Hz, 1H),7.57 (d, J=7.8 Hz, 1H), 7.81 (s, 1H), 7.96 (d, J=8.5 Hz, 1H), 10.75 (s,1H).

Example 24.N-(1-(1H-indol-3-yl)hexan-2-yl)-2-((3R,5R)-3,4,5-trimethylpiperazin-1-yl)thiazole-5-carboxamide

Step 1. Synthesis of tert-butyl(S)-(1-(dibenzylamino)-1-oxopropan-2-yl)carbamate

To a −30° C. solution of (tert-butoxycarbonyl)-L-alanine (5.00 g, 26.0mmol) in THF (100 mL) was added TEA (3.20 g, 31.0 mmol) and reactionmixture was added ClCO₂Bu-i (3.97 g, 29.0 mmol) dropwise. The reactionmixture was stirred at the same temperature for 30 min and then at roomtemperature for 5 h. The reaction mixture was cooled to 0° C. followedby dropwise addition of dibenzylamine (5.73 g, 29.0 mmol) and TEA (5.73g, 33.0 mmol) solution in THF (25 mL). The reaction mixture was stirredat room temperature for 48 h. The reaction mixture was quenched withsaturated NaHCO₃ (100 mL) and extracted with EtOAc (3×50 mL). Theorganic layer was separated, washed with brine (20 mL), dried overanhydrous Na₂SO₄, and concentrated in vacuo. The crude obtained waspurified by column chromatography (silica 100-200 mesh, 1 to 10% EtOAcin hexanes) and then triturated with hexanes (5 mL) to afford tert-butyl(S)-(1-(dibenzylamino)-1-oxopropan-2-yl)carbamate (6.17 g, 63%) as awhite solid. MS (ESI) m/e [M+H]⁺/Rt/%: 369.00/3.66/97.2%.

Step 2. Synthesis of (S)—N1,N1-dibenzylpropane-1,2-diamine

To a 0° C. solution of tert-butyl(S)-(1-(dibenzylamino)-1-oxopropan-2-yl)carbamate (5.50 g, 14.9 mmol) inDCM (17.8 mL) was added TFA (17.8 mL) dropwise. The reaction mixture wasstirred at room temperature for 18 h. The reaction mixture wasconcentrated in vacuo. The residue was diluted with DCM (75 mL) andwashed with saturated NaHCO₃ solution (100 mL). The organic layer wasseparated, dried over anhydrous Na₂SO₄, and concentrated in vacuo. Thecrude obtained was dissolved in THF (120 mL) followed by dropwiseaddition of BH₃-DMS (18.0 mL, 23.6 mmol) and the reaction mixture wasstirred at room temperature for 48 h. The reaction mixture was quenchedwith 10% HCl solution (20 mL) at 0° C. The reaction mixture was basifiedwith 50% NaOH solution (20 mL) and KOH (34.5 g) and heated at reflux for24 h. The reaction mixture was diluted with H₂O (50 mL) and extractedwith EtOAc (3×50 mL). The organic layer was separated, dried overanhydrous Na₂SO₄, and concentrated in vacuo. The crude obtained waspurified by column chromatography (silica, 100-200 mesh, 0 to 1% MeOH inDCM) to afford (S)—N1,N1-dibenzylpropane-1,2-diamine (3.00 g, 79%) as awhite semi solid. ¹H NMR (400 MHz, DMSO-d₆) δ 0.87 (d, J=6.3 Hz, 3H),1.40 (brs, 2H), 2.18 (d, J=6.3 Hz, 2H), 2.96-3.02 (m, 1H), 3.46 (s, 2H),3.56 (s, 2H), 7.19-7.38 (m, 10H).

Step 3. Synthesis of methyl((S)-1-(dibenzylamino)propan-2-yl)-L-alaninate

To a 0° C. solution of (S)—N1,N1-dibenzylpropane-1,2-diamine (0.90 g,3.54 mmol) in DCM (50 mL) was added TEA (1.00 g, 10.6 mmol) and themixture was stirred at 0° C. for 10 min followed by addition of methyl(R)-2-(((trifluoromethyl)sulfonyl)oxy)propanoate (1.30 g, 5.50 mmol).The reaction mixture was stirred at room temperature for 2 h. Thereaction mixture was quenched with saturated NaHCO₃ (20 mL) solution andextracted with DCM (3×20 mL). The organic layer was separated, driedover anhydrous Na₂SO₄, and concentrated in vacuo. The crude obtained waspurified by column chromatography (silica, 100-200 mesh, 2 to 12% EtOAcin hexanes) to afford methyl((S)-1-(dibenzylamino)propan-2-yl)-L-alaninate (1.15 g, 96%) as acolorless liquid. MS (ESI) m/e [M+H]⁺/Rt/%: 341.00/3.95/98.8%; ¹H NMR(400 MHz, CDCl₃) δ 0.94 (d, J=6.2 Hz, 3H), 1.22 (d, J=6.2 Hz, 3H),2.24-2.32 (m, 1H), 2.42-2.50 (m, 1H), 2.72-2.80 (m, 1H), 3.40-3.44 (m,1H), 3.50 (s, 2H), 3.59 (s, 2H), 3.71 (s, 3H), 7.21-7.36 (m, 10H).

Step 4. Synthesis of methylN—((S)-1-(dibenzylamino)propan-2-yl)-N-methyl-L-alaninate

A stirred solution of methyl((S)-1-(dibenzylamino)propan-2-yl)-L-alaninate (0.50 g, 1.40 mmol) andHCOOH (2.50 mL) in HCHO (2.50 mL) was heated in sealed tube at 80° C.for 6 h. The reaction mixture was quenched with saturated NaHCO₃ (40 mL)solution and extracted with EtOAc (4×25 mL). The organic layer wasseparated, dried over anhydrous Na₂SO₄, and concentrated in vacuo toafford methyl N—((S)-1-(dibenzylamino)propan-2-yl)-N-methyl-L-alaninate(0.49 g crude) as a yellow liquid. This compound was used as such forthe next reaction without further purification. MS (ESI) m/e[M+H]⁺/Rt/%: 355.00/4.19/90.5%; ¹H NMR (400 MHz, CDCl₃) δ 0.96 (d, J=6.5Hz, 1H), 1.09 (d, 6.7 Hz, 3H), 2.15 (s, 3H), 2.30-2.38 (m, 1H),2.48-2.54 (m, 1H), 2.98-3.08 (m, 1H), 3.40 (s, 2H), 3.44 (s, 2H),3.72-3.37 (m, 1H), 3.64 (s, 3H), 3.66-3.70 (m, 2H), 7.18-7.39 (m, 10H).

Step 5. Synthesis of (3S,5S)-1-benzyl-3,4,5-trimethylpiperazin-2-one

To a solution of methylN—((S)-1-(dibenzylamino)propan-2-yl)-N-methyl-L-alaninate (0.48 g, 1.35mmol) in EtOH (25 mL) was added 10% Pd/C (0.19 g) and cone. HCl (0.25mL). The reaction mixture was heated at 35° C. under hydrogen pressure(8 kg) for 16 h. The reaction mixture was filtered through diatomaceousearth, washing with EtOH (50 mL) and MeOH (50 mL). The filtrate wasconcentrated in vacuo to afford(3S,5S)-1-benzyl-3,4,5-trimethylpiperazin-2-one (0.35 g crude) as agreen liquid. This compound was used as such for the next reactionwithout further purification. MS (ESI) m/e [M+H]⁺/Rt/%:232.95/2.39/85.0%.

Step 6. Synthesis of (2S,6S)-4-benzyl-1,2,6-trimethylpiperazine

To a solution of LAH (0.16 g, 4.19 mmol) in THF (20 mL) was added(3S,5S)-1-benzyl-3,4,5-trimethylpiperazin-2-one (0.32 g, 1.39 mmol)portion wise and the reaction mixture was stirred at room temperaturefor 1 h. The reaction mixture was heated at reflux for 6 h. The reactionmixture was quenched with H₂O (2 mL), 15% NaOH (0.20 mL), and H₂O (0.7mL), and filtered, washing with excess THF. The organic layer wasseparated, dried over anhydrous Na₂SO₄, and concentrated in vacuo toafford (2S,6S)-4-benzyl-1,2,6-trimethylpiperazine (0.19 g crude) as acolorless liquid. This compound was used as such for the next reactionwithout further purification. MS (ESI) m/e [M+H]⁺/Rt/%:219.00/3.26/79.3%; ¹H NMR (400 MHz, DMSO-d₆) δ 1.36 (d, J=6.4 Hz, 6H),2.10 (s, 3H), 2.39-2.30 (m, 3H), 2.64-2.74 (m, 3H), 3.37 (s, 2H),7.19-7.36 (m, 5H).

Step 7. Synthesis of (2S,6S)-1,2,6-trimethylpiperazine

To a solution of (2S,6S)-4-benzyl-1,2,6-trimethylpiperazine (0.19 g,0.87 mmol) in MeOH (50 mL) was added Pd(OH)₂ (0.09 g) and the reactionmixture was heated at 40° C. under hydrogen pressure (8 kg) for 6 h. Thereaction mixture was filtered through diatomaceous earth, washing withMeOH (20 mL). The filtrate was concentrated in vacuo to afford(2S,6S)-1,2,6-trimethylpiperazine (0.12 g crude) as a colorless liquid.MS (ESI) m/e [M+H]⁺/Rt/%: 129.00/1.98/24.7%.

Step 8

To a solution of (2S,6S)-1,2,6-trimethylpiperazine (0.11 g, 0.20 mmol)and N-(1-(1H-indol-3-yl)hexan-2-yl)-2-bromothiazole-5-carboxamide (0.09g, 0.23 mmol) in CH₃CN (5 mL) was added K₂CO₃ (0.14 g, 1.00 mmol) andthe reaction mixture was heated in a sealed tube at 85° C. for 16 h. Thereaction mixture was concentrated in vacuo. The residue was diluted withH₂O (10 mL) and extracted with 10% MeOH in DCM (3×10 mL). The organiclayer was separated, dried over anhydrous Na₂SO₄, and concentrated invacuo. The crude obtained was purified by preparative HPLC to afford thetitle compound (0.015 g, 14%) as a white solid. HPLC Purity: 96.1%; MS(ESI) m/e [M+H]⁺/Rt/%: 454.00/2.66/98.4%; ¹H NMR (400 MHz, DMSO-d₆) δ0.80 (t, J=6.9 Hz, 3H), 0.95 (d, J=6.4 Hz, 6H), 1.16-1.60 (m, 6H), 2.22(s, 3H), 2.78-2.94 (m, 4H), 3.15 (dd, J=12.4, 6.3 Hz, 2H), 3.52 (d,J=10.9 Hz, 2H), 4.10-4.16 (m, 1H), 6.95 (t, J=7.5 Hz, 1H), 6.99-7.12 (m,2H), 7.31 (d, J=8.0 Hz, 1H), 7.57 (d, J=7.9 Hz, 1H), 7.76 (s, 1H), 7.91(d, J=8.6 Hz, 1H), 10.75 (s, 1H).

Example 42.N-(1-cyclobutyl-2-(1H-indol-3-yl)ethyl)-2-(4-methylpiperazin-1-yl)thiazole-5-carboxamide

Step 1. Synthesis of 1-cyclobutyl-2-(1H-indol-3-yl)ethan-1-one

To a 0° C. solution of 3-methyl-1H-indole (2.50 g, 19.0 mmol) inethylene dichloride (25 mL) was added AlCl₃ (12.6 g, 95.4 mmol) and thereaction mixture was stirred at 0° C. for 10 min and then heated at 45°C. for 30 min. The reaction mixture was cooled at 0° C. andcyclobutanecarbonyl chloride (4.50 g, 38.1 mmol) was added dropwise. Thereaction mixture was stirred at room temperature for 16 h. The reactionmixture was poured in to ice cold H₂O (200 mL) and extracted with DCM(3×100 mL). The organic layer was separated, dried over anhydrous Na₂SO₄and concentrated in vacuo. The crude obtained was purified by columnchromatography (silica, 100-200 mesh, 0 to 10% EtOAc in hexanes) toafford 1-cyclobutyl-2-(1H-indol-3-yl)ethan-1-one (2.01 g, 50%) as lightgreen liquid. MS (ESI) m/e [M+H]⁺/Rt/%: 214.00/3.20/92.3%; ¹H NMR (400MHz, DMSO-d₆) δ 1.62-1.73 (m, 1H), 1.79-1.89 (m, 1H), 1.93-2.01 (m, 2H),2.04-2.13 (m, 2H), 3.39 (t, J=8.3 Hz, 1H), 3.72 (s, 2H), 6.92-6.99 (m,1H), 7.05 (t, J=7.6 Hz, 1H), 7.20 (s, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.39(d, J=7.8 Hz, 1H), 10.91 (brs, 1H).

Step 2. Synthesis of 1-cyclobutyl-2-(1H-indol-3-yl)ethan-1-aminehydrochloride

To a solution of 1-cyclobutyl-2-(1H-indol-3-yl)ethan-1-one (1.90 g, 8.92mmol) in MeOH (50 mL) was added NH₄OAc (5.83 g, 75.8 mmol) and thereaction mixture was stirred at room temperature for 10 min. NaBH₃CN(0.84 g, 13.3 mmol) was added and the reaction mixture was stirred atroom temperature for 10 min and then was heated at reflux for 16 h. Thereaction mixture was concentrated in vacuo. The residue was acidifiedwith 3 N HCl, decanted, and dried in vacuo. The crude obtained waspurified by triturating with pentane (50 mL) to afford1-cyclobutyl-2-(1H-indol-3-yl)ethan-1-amine hydrochloride (1.80 g crude)as a brown semi solid. MS (ESI) m/e [M+H]⁺/Rt/%: 215.00/3.21/96.0%; ¹HNMR (400 MHz, DMSO-d₆) δ 1.66-2.01 (m, 6H), 2.40-2.46 (m, 1H), 2.91 (d,J=6.4 Hz, 2H), 6.97-7.03 (m, 1H), 7.07-7.13 (m, 1H), 7.22-7.29 (m, 1H),7.37 (d, J=8.3 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.88 (brs, 2H), 11.02(brs, 1H).

Step 3

To a solution of 2-(4-methylpiperazin-1-yl)thiazole-5-carboxylic acid(0.24 g, 1.05 mmol) in DMF (10 mL), HATU (0.43 g, 1.14 mmol) and DIPEA(0.47 mL, 2.63 mmol) were added and the reaction mixture was stirred atroom temperature for 10 min. 1-cyclobutyl-2-(1H-indol-3-yl)ethan-1-aminehydrochloride (0.25 g, 0.87 mmol) was added and the reaction mixture wasstirred in sealed tube at room temperature for 16 h. The reactionmixture was diluted with H₂O (100 mL) and extracted with EtOAc (3×100mL). The organic layer was separated, washed with H₂O (2×100 mL), brine(75 mL), dried over anhydrous Na₂SO₄, and concentrated in vacuo. Thecrude obtained was purified by column chromatography (silica, 230-400mesh, 0 to 5% MeOH in DCM) to afford the title compound (0.16 g, 45%) asan off-white solid. HPLC Purity: 97.3%; MS (ESI) m/e [M+H]⁺/Rt/%:424.00/2.59/96.9%; ¹H NMR (400 MHz, DMSO-d₆) δ 0.86 (m, 1H), 1.23-1.33(m, 1H), 1.67-1.97 (m, 5H), 2.22 (s, 3H), 2.40-2.46 (m, 4H), 2.71-2.88(m, 2H), 3.39-3.48 (m, 4H), 4.06-4.22 (m, 1H), 6.91-6.98 (m, 1H),7.01-7.08 (m, 2H), 7.30 (d, J=7.8 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.79(s, 1H), 7.84 (d, J=8.8 Hz, 1H), 10.72 (brs, 1H).

Example 43.N-(1-cyclohexyl-2-(1H-indol-3-yl)ethyl)-2-(4-methylpiperazin-1-yl)thiazole-5-carboxamide

Step 1. Synthesis of 1-cyclohexyl-2-(1H-indol-3-yl)ethan-1-one

To a solution of 3-methyl-1H-indole (5.00 g, 38.1 mmol) in EDC (50 mL),AlCl₃ (25.0 g, 190 mmol) was added at 0° C. and the reaction mixture wasstirred at 0° C. for 10 min and then was heated at 45° C. for 30 min.The reaction mixture was cooled at 0° C. followed by dropwise additionof cyclohexanecarbonyl chloride (8.30 g, 56.0 mmol). The reactionmixture was stirred at room temperature for 16 h. The reaction mixturewas poured in to ice cold H₂O (300 mL) and extracted with DCM (3×150mL). The organic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The crude obtained was purified by columnchromatography (silica, 100-200 mesh, 0 to 12% EtOAc in hexanes) toafford 1-cyclohexyl-2-(1H-indol-3-yl)ethan-1-one (2.20 g, 24%) as lightbrown liquid. MS (ESI) m/e [M+H]⁺/Rt/%: 242.00/3.39/92.1%; ¹H NMR (400MHz, DMSO-d₆) δ 1.13-1.27 (m, 6H), 1.57 (d, J=9.8 Hz, 1H), 1.66 (d,J=5.9 Hz, 2H), 1.76 (d, J=9.8 Hz, 2H), 3.82 (s, 2H), 6.91-6.98 (m, 1H),7.05 (t, J=7.3 Hz, 1H), 7.19 (s, 1H), 7.35 (dd, J=17.4, 8.1 Hz, 2H),10.89 (brs, 1H).

Step 2. Synthesis of 1-cyclohexyl-2-(1H-indol-3-yl)ethan-1-aminehydrochloride

To a solution of 1-cyclohexyl-2-(1H-indol-3-yl)ethan-1-one (0.50 g, 2.07mmol) in MeOH (20 mL), NH₄OAc (1.27 g, 16.5 mmol) was added and thereaction mixture was stirred at room temperature for 10 min. NaBH₃CN(0.19 g, 3.10 mmol) was added and the reaction mixture was stirred atroom temperature for 10 min and then was heated at reflux for 16 h. Thereaction mixture was concentrated in vacuo. The residue was acidifiedwith 3 N HCl, decanted, and dried in vacuo. The crude obtained waspurified by triturating with pentane (250 mL) to afford1-cyclohexyl-2-(1H-indol-3-yl)ethan-1-amine hydrochloride (0.43 g crude)as a light brown solid. MS (ESI) m/e [M+H]⁺/Rt/%: 243.00/3.78/82.6%; ¹HNMR (400 MHz, DMSO-d₆) δ 1.10-1.33 (m, 6H), 1.56-1.81 (m, 5H), 2.92-2.99(m, 1H), 2.99-3.07 (m, 1H), 3.20-3.26 (m, 1H), 6.98-7.05 (m, 1H),7.07-7.13 (m, 1H), 7.27 (d, J=2.0 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.55(d, J=7.8 Hz, 1H), 7.86 (brs, 3H), 11.00 (brs, 1H).

Step 3

To a solution of 2-(4-methylpiperazin-1-yl)thiazole-5-carboxylic acid(0.26 g, 1.14 mmol) in DMF (10 mL), HATU (0.47 g, 2.85 mmol) and DIPEA(0.51 mL, 2.85 mmol) were added and the reaction mixture was stirred atroom temperature for 10 min. 1-cyclohexyl-2-(1H-indol-3-yl)ethan-1-aminehydrochloride (0.30 g, 0.95 mmol) was added and the reaction mixture wasstirred in sealed tube at room temperature for 16 h. The reactionmixture was diluted with H₂O (100 mL) and extracted with EtOAc (3×100mL). The organic layer was separated, washed with H₂O (2×100 mL), brine(75 mL), dried over anhydrous Na₂SO₄, and concentrated in vacuo. Thecrude obtained was purified by column chromatography (silica, 230-400mesh, 0 to 5% MeOH in DCM) to afford the title compound (0.12 g, 28%) asan off-white solid. HPLC Purity: 95.8%; MS (ESI) m/e [M+H]⁺/Rt/%:452.00/2.46/96.8%; ¹H NMR (400 MHz, DMSO-d₆) δ 1.03-1.19 (m, 5H),1.47-1.82 (m, 6H), 2.20 (s, 3H), 2.32-2.38 (m, 4H), 2.80 (dd, J=14.7,9.8 Hz, 1H), 2.94-3.04 (m, 1H), 3.38-3.44 (m, 4H), 3.91-4.09 (m, 1H),6.90-6.96 (m, 1H), 7.00-7.07 (m, 2H), 7.28 (d, J=7.8 Hz, 1H), 7.50 (d,J=7.8 Hz, 1H), 7.78-7.84 (m, 2H), 10.68 (brs, 1H).

Example 63.N-(1-(1H-indol-3-yl)propan-2-yl)-2-(4-methylpiperazin-1-yl)thiazole-5-carboxamide

Step 1. Synthesis of 3-(2-nitroprop-1-en-1-yl)-1H-indole

To a solution of 1H-indole-3-carbaldehyde (3.00 g, 20.6 mmol) in CH₃COOH(20.6 mL) and nitroethane (50 mL) was added NH₄OAc (0.78 g, 1.00 mmol)and the reaction mixture was heated at 110° C. for 8 h. The reactionmixture was cooled to 0° C. and filtered. The crude obtained waspurified by column chromatography (silica 100-200 mesh, 10 to 40% EtOAcin hexanes) to afford 3-(2-nitroprop-1-en-1-yl)-1H-indole (2.50 g, 60%)as a red solid. ¹H NMR (400 MHz, DMSO-d₆) δ 2.54 (s, 3H), 7.22-7.40 (m,2H), 7.44-7.50 (m, 1H), 7.73-7.88 (m, 2H), 7.52 (s, 1H), 8.70 (brs, 1H).

Step 2. Synthesis of 1-(1H-indol-3-yl)propan-2-amine

To a suspension of LAH (2.60 g, 69.3 mmol) in dry THF (25 mL) was addeda solution of 3-(2-nitroprop-1-en-1-yl)-1H-indole (2.00 g, 9.90 mmol) inTHF (10 mL) dropwise and the reaction mixture was heated at reflux for 6h. The reaction mixture was diluted with EtOAc (200 mL). The reactionmixture was cooled to 0° C., quenched with saturated Na₂SO₄ (10 mL), andfiltered. The organic layer was separated, dried over anhydrous Na₂SO₄,and concentrated in vacuo. The crude obtained was washed with pentane(10 mL) to afford 1-(1H-indol-3-yl)propan-2-amine (1.20 g, 70%) as anoff-white solid. MS (ESI) m/e [M+H]⁺/Rt/%: 175.00/2.78/39.6%.

Step 3. Synthesis ofN-(1-(1H-indol-3-yl)propan-2-yl)-2-bromothiazole-5-carboxamide

To a solution of 1-(1H-indol-3-yl)propan-2-amine (1.00 g, 4.80 mmol) and2-bromothiazole-5-carboxylic acid (1.16 g, 8.72 mmol) in DMF (20 mL) wasadded 2-chloro-1-methylpyridinium iodide (Mukaiyama reagent; 1.83 g,7.20 mmol) followed by addition of DIPEA (2.19 g, 16.8 mmol). Thereaction mixture was stirred at room temperature for 16 h.

The reaction mixture was diluted with H₂O (50 mL) and extracted with DCM(3×20 mL). The organic layer was separated, dried over anhydrous Na₂SO₄,and concentrated in vacuo. The crude obtained was purified by columnchromatography (silica 1000-200 mesh, 0.1 to 0.4% MeOH in DCM) andtriturating with pentane (10 mL) to affordN-(1-(1H-indol-3-yl)propan-2-yl)-2-bromothiazole-5-carboxamide (0.35 g,20%) as a brown solid. MS (ESI) m/e [M+H+1]⁺/Rt/%: 366.00/2.97/95.5%; ¹HNMR (400 MHz, CDCl₃) δ 1.29 (d, J=6.9 Hz, 3H), 3.06 (d, J=5.7 Hz, 2H),4.48-4.56 (m, 1H), 5.86 (d, J=7.4 Hz, 1H), 7.08 (d, J=2.1 Hz, 1H),7.10-7.26 (m, 2H), 7.41 (d, J=8.1 Hz, 1H), 7.58 (s, 1H), 7.61-7.65 (m,1H), 8.14 (s, 1H).

Step 4. To a solution ofN-(1-(1H-indol-3-yl)propan-2-yl)-2-bromothiazole-5

carboxamide (0.15 g, 0.41 mmol) and 1-methylpiperazine (0.06 g, 0.61mmol) in CH₃CN (5 mL) was added K₂CO₃ (0.17 g, 1.20 mmol) and thereaction mixture was heated in sealed tube at 100° C. for 16 h. Thereaction mixture was concentrated in vacuo. The residue was diluted withH₂O (10 mL) and extracted with 10% MeOH in DCM (3×10 mL). The organiclayer was separated, dried over anhydrous Na₂SO₄, and concentrated invacuo. The crude obtained was purified by combi-flash columnchromatography (0.1 to 1% MeOH in DCM) and triturating with DCM:pentane(1:10, 10 mL) to afford the title compound (0.068 g, 43%) as a whitesolid. HPLC Purity: 99.1%; MS (ESI) m/e [M+H]⁺/Rt/%: 384.00/2.16/98.0%;¹H NMR (400 MHz, DMSO-d₆) δ 1.12 (d, J=6.5 Hz, 3H), 2.21 (s, 3H),2.36-2.43 (m, 4H), 2.76 (dd, J=14.1, 7.3 Hz, 1H), 2.96 (dd, J=14.1, 6.2Hz, 1H), 3.40-3.47 (m, 4H), 4.16-4.22 (m, 1H), 6.96 (t, J=7.4 Hz, 1H),7.00-7.14 (m, 2H), 7.32 (d, J=8.0 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.80(s, 1H), 8.04 (d, J=7.9 Hz, 1H), 10.78 (s, 1H).

Example 64.N-(1-(1H-indol-3-yl)butan-2-yl)-2-(4-methylpiperazin-1-yl)thiazole-5-carboxamide

Step 1. Synthesis of 3-(2-nitrobut-1-en-1-yl)-1H-indole

To a solution of 1H-indole-3-carbaldehyde (3.00 g, 20.0 mmol) innitropropane (30 mL) was added NH₄OAc (1.84 g, 24.0 mmol) and thereaction mixture was heated at 100° C. for 18 h. The reaction mixturewas concentrated in vacuo. The residue was diluted with H₂O (50 mL) andextracted with EtOAc (3×50 mL). The organic layer was separated, washedwith brine (200 mL), dried over anhydrous Na₂SO₄, and concentrated invacuo. The crude obtained was purified by washing with pentane (20 mL)to afford 3-(2-nitrobut-1-en-1-yl)-1H-indole (4.48 g, 62%) as an orangesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.20 (t, J=7.3 Hz, 3H), 2.94 (q,J=7.3 Hz, 2H), 7.17-7.32 (m, 2H), 7.49-7.59 (m, 1H), 7.83 (d, J=7.8 Hz,1H), 7.99 (s, 1H), 8.41 (s, 1H), 12.19 (brs, 1H).

Step 2. Synthesis of 1-(1H-indol-3-yl)butan-2-amine

To a solution of 3-(2-nitrobut-1-en-1-yl)-1H-indole (0.60 g, 2.77 mmol)in THF (60 mL) was added LAH (0.42 g, 11.1 mmol) and the reactionmixture was heated at 70° C. for 5 h. An additional portion of LAH (0.42g, 11.1 mmol) was added and the reaction mixture was heated at 70° C.for a further 16 h.

The reaction mixture was cooled to 0° C., quenched with saturated Na₂SO₄(20 mL), and diluted with EtOAc (150 mL). The reaction mixture wasstirred for 10 min, filtered through diatomaceous earth, and thefiltrate was concentrated in vacuo. The crude obtained was purified bywashing with pentane (10 mL) and dried in vacuo to afford1-(1H-indol-3-yl)butan-2-amine (0.60 g crude) as a brown semisolid. MS(ESI) m/e [M+H]⁺/Rt/%: 189.00/3.02/45.3%.

Step 3. Synthesis ofN-(1-(1H-indol-3-yl)butan-2-yl)-2-bromothiazole-5-carboxamide

To a solution of 1-(1H-indol-3-yl)butan-2-amine (0.60 g, 3.40 mmol) and2-bromothiazole-5-carboxylic acid (0.79 g, 3.40 mmol) in DMF (10 mL) wasadded Mukaiyama reagent (1.21 g, 4.70 mmol) followed by addition ofDIPEA (1.22 g, 9.50 mmol). The reaction mixture was stirred at roomtemperature for 16 h. The reaction mixture was diluted with H₂O (25 mL)and extracted with DCM (3×10 mL). The organic layer was separated, driedover anhydrous Na₂SO₄, and concentrated in vacuo. The crude obtained waspurified by column chromatography (silica 100-200 mesh, 1 to 15% EtOAcin hexanes) to affordN-(1-(1H-indol-3-yl)butan-2-yl)-2-bromothiazole-5-carboxamide (0.26 g,21%) as a brown solid. MS (ESI) m/e [M+H+1]/Rt/%: 380.00/3.09/77.1%; ¹HNMR (400 MHz, DMSO-d₆) δ 0.85 (t, J=7.3 Hz, 3H), 1.42-1.53 (m, 1H),1.57-1.66 (m, 1H), 2.85 (q, J=7.3 Hz, 2H), 3.96-4.10 (m, 1H), 6.89-6.97(m, 1H), 7.03 (t, J=7.6 Hz, 1H), 7.10 (s, 1H), 7.30 (d, J=7.8 Hz, 1H),7.55 (d, J=7.8 Hz, 1H), 8.20-8.24 (m, 1H), 8.49 (d, J=8.3 Hz, 1H), 10.77(brs, 1H).

Step 4

To a solution ofN-(1-(1H-indol-3-yl)butan-2-yl)-2-bromothiazole-5-carboxamide (0.25 g,0.66 mmol) and 1-methylpiperazine (0.08 g, 0.79 mmol) in CH₃CN (6 mL)was added K₂CO₃ (0.27 g, 1.98 mmol) and the reaction mixture was heatedat 100° C. for 16 h. The reaction mixture was concentrated in vacuo. Theresidue was diluted with H₂O (10 mL) and extracted with 5% MeOH in DCM(3×10 mL). The organic layer was separated, dried over anhydrous Na₂SO₄,and concentrated in vacuo. The crude obtained was purified by columnchromatography (silica 230-400 mesh, 0.5 to 4% MeOH in DCM) and bypreparative HPLC to afford the title compound (0.06 g, 22%) as a whitesolid. HPLC Purity: 99.8%; MS (ESI) m/e [M+H]⁺/Rt/%: 398.00/2.32/99.2%;¹H NMR (400 MHz, DMSO-d₆) δ 0.85 (t, J=7.3 Hz, 3H), 1.42-1.48 (m, 1H),1.54-1.64 (m, 1H), 2.21 (s, 3H), 2.44-2.54 (m, 4H), 2.78-2.94 (m, 2H),3.41-3.49 (m, 4H), 4.00-4.08 (m, 1H), 6.92-6.99 (m, 1H), 7.04 (t, J=7.3Hz, 1H), 7.10 (d, J=2.0 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.56-7.61 (m,1H), 7.81 (s, 1H), 7.93 (d, J=8.3 Hz, 1H), 10.76 (brs, 1H).

Example 65.N-(1-(1H-indol-3-yl)pentan-2-yl)-2-(4-methylpiperazin-1-yl)thiazole-5-carboxamide

Step 1. Synthesis of 1-nitrobutane

To a solution of AgNO₂ (18.8 g, 122 mmol) in Et₂O (200 mL), 1-iodobutane(15.0 g, 81.0 mmol) was added and the reaction mixture was stirred insealed tube at room temperature for 16 h. The reaction mixture wasfiltered through diatomaceous earth, washing with Et₂O (100 mL). Thefiltrate was concentrated in vacuo to afford 1-nitrobutane (9.00 gcrude) as a light brown liquid. This compound was used as such for thenext reaction without further purification. ¹H NMR (400 MHz, CDCl₃) δ0.98 (t, J=7.3 Hz, 3H), 1.38-1.48 (m, 2H), 1.98-2.08 (m, 2H), 4.39 (t,J=6.8 Hz, 2H).

Step 2. Synthesis of 3-(2-nitropent-1-en-1-yl)-1H-indole

To a solution of 1-nitrobutane (8.50 g, 82.5 mmol) and1H-indole-3-carbaldehyde (2.00 g, 13.7 mmol) in CH₃COOH (5 mL), NH₄OAc(1.60 g, 20.6 mmol) was added and the reaction mixture was heated insealed tube at 100° C. for 15 h. The reaction mixture was concentratedin vacuo. The residue was basified to pH 8 with saturated NaHCO₃solution (30 mL) and extracted with EtOAc (2×200 mL). The organic layerwas separated, dried over anhydrous Na₂SO₄, and concentrated in vacuo.The crude obtained was purified by column chromatography (silica,100-200 mesh, 10 to 20% EtOAc in hexanes) to afford3-(2-nitropent-1-en-1-yl)-1H-indole (0.80 g, 25%) as a yellow solid. MS(ESI) m/e [M+H]⁺/Rt/%: 231.00/3.57/89.9%; ¹H NMR (400 MHz, DMSO-d₆) δ1.03 (t, J=7.6 Hz, 3H), 1.60-1.70 (m, 2H), 2.90-2.97 (m, 2H), 7.18-7.29(m, 2H), 7.52 (d, J=7.8 Hz, 1H), 7.83 (d, J=7.3 Hz, 1H), 7.95 (s, 1H),8.44 (s, 1H), 12.13 (brs, 1H).

Step 3. Synthesis of 1-(1H-indol-3-yl)pentan-2-amine

To a suspension of 3-(2-nitropent-1-en-1-yl)-1H-indole (0.80 g, 3.47mmol) in THF (30 mL), LAH (0.66 g, 17.3 mmol) was added lot wise at 0°C. and the reaction mixture was stirred at room temperature for 1 h andthen was heated at reflux for 6 h. The reaction mixture was quenchedwith saturated Na₂SO₄ (5 mL) and EtOAc (50 mL). The reaction mixture wasfiltered through diatomaceous earth, washing with EtOAc (20 mL). Thefiltrate was concentrated in vacuo to afford1-(1H-indol-3-yl)pentan-2-amine (0.58 g crude) as a brown liquid. Thiscompound was used as such for the next reaction without furtherpurification. MS (ESI) m/e [M+H]⁺/Rt/%: 203.00/3.16/65.1%.

Step 4

To a solution of 2-(4-methylpiperazin-1-yl)thiazole-5-carboxylic acid(0.30 g, 1.32 mmol) in DMF (8 mL), HATU (1.00 g, 2.64 mmol) was addedfollowed by addition of DIPEA (0.70 mL, 3.96 mmol). The reaction mixturewas stirred at room temperature for 10 min followed by addition of1-(1H-indol-3-yl)pentan-2-amine (0.32 g, 1.58 mmol) solution in DMF (1.8mL). The reaction mixture was stirred at room temperature for 5 h. Thereaction mixture was diluted with H₂O (100 mL) and extracted with EtOAc(2×100 mL). The organic layer was separated, washed with H₂O (200 mL),brine (200 mL), dried over anhydrous Na₂SO₄, and concentrated in vacuo.The crude obtained was purified by column chromatography (silica,100-200 mesh, 0 to 10% MeOH in DCM) and preparative HPLC to afford thetitle compound (0.13 g, 25%) as an off-white solid. HPLC Purity: 99.0%;MS (ESI) m/e [M+H]⁺/Rt/%: 412.00/2.49/97.0%; ¹H NMR (400 MHz, DMSO-d₆) δ0.81 (t, J=7.3 Hz, 3H), 1.16-1.28 (m, 1H), 1.36-1.44 (m, 1H), 1.50-1.58(m, 2H), 2.21 (s, 3H), 2.36-2.43 (m, 4H), 2.75-2.93 (m, 2H), 3.39-3.47(m, 4H), 4.05-4.20 (m, 1H), 6.93-6.98 (m, 1H), 7.04 (t, J=7.6 Hz, 1H),7.09 (d, J=2.0 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H),7.81 (s, 1H), 7.96 (d, J=8.3 Hz, 1H), 10.77 (brs, 1H).

Example 66.N-(1-(1H-indol-3-yl)-4-methylpentan-2-yl)-2-(4-methylpiperazin-1-yl)thiazole-5-carboxamide

The title compound was prepared using a method analogous to thatdescribed for Example 65. HPLC Purity: 96.1%; MS (ESI) m/e [M+H]⁺/Rt/%:426.00/2.65/98.9%; ¹H NMR (400 MHz, DMSO-d₆) δ 0.77 (d, J=6.4 Hz, 3H),0.84 (d, J=6.8 Hz, 3H), 1.27-1.34 (m, 1H), 1.44-1.53 (m, 1H), 1.57-1.69(m, 1H), 2.21 (s, 3H), 2.38-2.42 (m, 4H), 2.76-2.92 (m, 2H), 3.40-3.47(m, 4H), 4.14-4.29 (m, 1H), 6.93-6.99 (m, 1H), 7.04 (t, J=7.6 Hz, 1H),7.09 (d, J=1.5 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H),7.79 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 10.75 (brs, 1H).

Example 67.N-(1-cyclobutyl-3-(1H-indol-3-yl)propan-2-yl)-2-(4-methylpiperazin-1-yl)thiazole-5-carboxamide

The title compound was prepared using methods analogous to thosedescribed in the preceding examples. HPLC Purity: 99.2%; MS (ESI) m/e[M+H]⁺/Rt/%: 438.00/2.66/98.9%; ¹H NMR (400 MHz, DMSO-d₆) δ 1.41-1.50(m, 1H), 1.60-1.62 (m, 2H), 1.63-1.81 (m, 3H), 1.89-1.98 (m, 2H), 2.23(s, 3H), 2.28-2.36 (m, 1H), 2.38-2.44 (m, 4H), 2.74-2.93 (m, 2H),3.42-3.46 (m, 4H), 4.03-4.15 (m, 1H), 6.93-6.98 (m, 1H), 7.04 (t, J=7.6Hz, 1H), 7.08 (s, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.56 (d, J=7.8 Hz, 1H),7.78 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 10.76 (brs, 1H).

Example 68.N-(1-(1H-indol-3-yl)hexan-2-yl)-2-(4-methyl-2-oxopiperazin-1-yl)thiazole-5-carboxamide

Step 1

To a solution ofN-(1-(1H-indol-3-yl)hexan-2-yl)-2-bromothiazole-5-carboxamide (0.10 g,0.24 mmol) and 4-methylpiperazin-2-one (0.03 g, 0.29 mmol) in dioxane (7mL), Cs₂CO₃ (0.23 g, 0.72 mmol) and2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl(BrettPhos precatalyst; 0.02 g, 0.02 mmol) were added. The reactionvessel was purged with argon for 20 min and the mixture was then heatedat 110° C. for 16 h. The reaction mixture was filtered throughdiatomaceous earth, washing with 5% MeOH in DCM (2×10 mL). The filtratewas concentrated, and the crude obtained was purified by columnchromatography (silica, 100-200 mesh, 1 to 4% MeOH in DCM) andpreparative HPLC to afford the title compound (0.03 g, 14%) as a whitesolid. HPLC Purity: 99.4%; MS (ESI) m/e [M+H]⁺/Rt/%: 440.00/2.69/98.0%;¹H NMR (400 MHz, DMSO-d₆) δ 0.81 (t, J=6.8 Hz, 3H), 1.19-1.35 (m, 4H),1.47-1.63 (m, 2H), 2.31 (s, 3H), 2.81 (t, J=5.4 Hz, 2H), 2.85-2.97 (m,2H), 3.34 (s, 2H), 4.03 (t, J=5.6 Hz, 2H), 4.16 (m, 1H), 6.92-6.98 (m,1H), 7.04 (t, J=7.6 Hz, 1H), 7.11 (d, J=1.5 Hz, 1H), 7.31 (d, J=8.3 Hz,1H), 7.58 (d, J=7.8 Hz, 1H), 8.13 (s, 1H), 8.24 (d, J=8.8 Hz, 1H), 10.75(brs, 1H).

Example 69.N-(1-(5-methyl-1H-indol-3-yl)hexan-2-yl)-2-(4-methylpiperazin-1-yl)thiazole-5-carboxamide

The title compound was prepared starting from 1-nitropentane (preparedfrom 1-iodopentane as described above) and5-methyl-1H-indole-3-carbaldehyde using methods analogous to thosedescribed herein. HPLC Purity: 99.8%; MS (ESI) m/e [M+H]⁺/Rt/%:440.00/2.78/96.0%; ¹H NMR (400 MHz, DMSO-d₆) δ 0.83 (d, J=6.4 Hz, 3H),1.21-1.34 (m, 4H), 1.46-1.55 (m, 2H), 2.21 (s, 3H), 2.32 (s, 3H),2.32-2.42 (m, 4H), 2.78-2.90 (m, 2H), 3.40-3.48 (m, 4H), 4.05-4.11 (m,1H), 6.86 (d, J=8.2 Hz, 1H), 7.03 (s, 1H), 7.18 (d, J=8.2 Hz, 1H), 7.33(s, 1H), 7.80 (s, 1H), 7.91 (d, J=8.5 Hz, 1H), 10.61 (s, 1H).

Example 70.N-(1-(5,7-dibromo-1H-indol-3-yl)hexan-2-yl)-2-(4-methylpiperazin-1-yl)thiazole-5-carboxamide

Step 1. Synthesis of 5,7-dibromo-1H-indole

To a solution of 2,4-dibromo-1-nitrobenzene (15.0 g, 53.3 mmol) in THF(150 mL), vinylmagnesium bromide (21.0 g, 160 mmol) was added at −40° C.and the reaction mixture was stirred at −40° C. for 30 min. The reactionmixture was poured into saturated solution of NH₄Cl (300 mL) andextracted with EtOAc (3×300 mL). The organic layer was separated, washedwith brine (200 mL), dried over anhydrous Na₂SO₄, and concentrated invacuo. The crude obtained was purified by column chromatography (silica,100-200 mesh, 0 to 8% EtOAc in hexanes) to afford 5,7-dibromo-1H-indole(5.90 g, 41%) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 6.56 (d,J=2.4 Hz, 1H), 7.43-7.52 (m, 2H), 7.78 (s, 1H), 11.57 (brs, 1H).

Step 2. Synthesis of 5,7-dibromo-1H-indole-3-carbaldehyde

POCl₃ (4.90 mL, 50.9 mmol) was added dropwise to a stirred solution ofDMF (24 mL) at 0° C. and the reaction mixture was stirred at sametemperature for 10 min. 5,7-dibromo-1H-indole (5.60 g, 20.3 mmol)solution in DMF (56 mL) was added dropwise at 0° C. and the reactionmixture was stirred at 0° C. for 10 min and then at room temperature for3 h. The reaction mixture was diluted with 3.8 M KOH solution (11.4 g,203 mmol) dropwise and the reaction mixture was heated at reflux for 16h. The reaction mixture was poured in to saturated solution of NaHCO₃(300 mL) and extracted with EtOAc (3×150 mL). The organic layer wasseparated, washed with H₂O, dried over anhydrous Na₂SO₄, andconcentrated in vacuo. The crude obtained was washed with pentane (2×60mL) and dried in vacuo to afford 5,7-dibromo-1H-indole-3-carbaldehyde(5.92 g, 97%) as a brown solid. This compound was used as such for thenext reaction without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ7.69 (d, J=0.98 Hz, 1H), 8.23 (d, J=0.98 Hz, 1H), 8.42 (s, 1H), 9.95 (s,1H), 12.60 (brs, 1H).

Step 3. Synthesis of (E)-5,7-dibromo-3-(2-nitrohex-1-en-1-yl)-1H-indole

The title compound (0.69 g, 35%) was obtained as a yellow solid from5,7-dibromo-1H-indole-3-carbaldehyde (1.50 g, 4.98 mmol) and1-nitropentane (4.37 g, 37.3 mmol) as described in the precedingexamples. ¹H NMR (400 MHz, DMSO-d₆) δ 0.93 (t, J=7.1 Hz, 3H), 1.39-1.47(m, 2H), 1.55 (m, 2H), 2.86-2.97 (m, 2H), 7.65 (s, 1H), 7.87 (s, 1H),8.17 (s, 1H), 8.32 (s, 1H), 12.55 (brs, 1H).

Step 4. Synthesis of 5,7-dibromo-3-(2-nitrohexyl)-1H-indole

To a solution of (E)-5,7-dibromo-3-(2-nitrohex-1-en-1-yl)-1H-indole(0.41 g, 1.02 mmol) in toluene (13 mL), was added diethyl2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (0.77 g, 3.07 mmol)followed by addition of silica (0.77 g) and the reaction mixture washeated in sealed tube at 120° C. for 16 h. The reaction mixture wasconcentrated in vacuo. The crude obtained was purified by columnchromatography (silica, 100-200 mesh, 0 to 10% EtOAc in hexanes) toafford 5,7-dibromo-3-(2-nitrohexyl)-1H-indole (0.89 g crude) as a yellowsemi solid. MS (ESI) m/e [M+H]⁺/Rt/%: 405.00/3.96/42.5%.

Step 5. Synthesis of 1-(5,7-dibromo-1H-indol-3-yl)hexan-2-amine

To a solution of 5,7-dibromo-3-(2-nitrohexyl)-1H-indole (0.89 g, 2.21mmol) in MeOH (10 mL), Zn (0.72 g, 11.0 mmol) was added followed byNH₄Cl (0.59 g, 11.0 mmol) and the reaction mixture was stirred at roomtemperature for 2 h. Additional Zn (0.29 g, 4.42 mmol) and NH₄Cl (0.23g, 11.0 mmol) were added and the reaction mixture was stirred at roomtemperature for 30 min. The reaction mixture was filtered throughdiatomaceous earth, washing with MeOH (3×30 mL), and the filtrate wasconcentrated in vacuo. The residue was diluted with H₂O (50 mL) andextracted with EtOAc (3×75 mL). The organic layer was separated, washedwith brine (50 mL), dried over anhydrous Na₂SO₄, and concentrated invacuo. The crude obtained was dissolved in DCM (5 mL), recrystallizedwith pentane (20 mL), filtered, and dried in vacuo to afford1-(5,7-dibromo-1H-indol-3-yl)hexan-2-amine (0.28 g crude) as anoff-white solid. The product was used in the following step withoutfurther purification.

Step 6

The title compound was prepared from2-(4-methylpiperazin-1-yl)thiazole-5-carboxylic acid (0.20 g, 0.90 mmol)and 1-(5,7-dibromo-1H-indol-3-yl)hexan-2-amine (0.28 g, 0.75 mmol) asdescribed in the preceding examples. The crude product was purified toan off-white solid by column chromatography (silica, 230-400 mesh, 0 to4% MeOH in DCM) and by preparative HPLC (0.33 g, 34%). HPLC Purity:99.7%; MS (ESI) m/e [M+H]⁺/Rt/%: 582.00/3.10/99.5%; ¹H NMR (400 MHz,DMSO-d₆) δ 0.86 (t, J=6.6 Hz, 3H), 1.19-1.35 (m, 4H), 1.40-1.52 (m, 2H),2.20 (s, 3H), 2.32-2.38 (m, 4H), 2.82 (d, J=6.4 Hz, 2H), 3.40-3.51 (m,4H), 3.96-4.02 (m, 1H), 7.22 (s, 1H), 7.40 (s, 1H), 7.75 (s, 1H), 7.81(s, 1H), 7.90 (d, J=8.3 Hz, 1H), 11.24 (brs, 1H).

The remaining examples may be prepared using methods analogous to thosedescribed herein.

Biological Example 1: In-Vitro Fluorescence Polarization Assay withAlpha-Synuclein Peptide Fragment (4F)

The fluorescence polarization assay tests the ability of compounds toinhibit the self-aggregation of α-synuclein peptide fragments. Peptideswere incubated for 120 min at room temperature in the presence orabsence of test compounds (compound concentrations were 33.3 to 0.015μM). Samples were read on a Beckman Coulter DTX 880 plate reader influorescence polarization mode using excitation at 485 nm and emissionat 520 nm. Data was analyzed using a four-parameter logistic fit (XLFit,IDBS Software). Peptide 4F (CTGFVKKDQLGK (SEQ ID NO: 1)) was prepared byAmerican Peptide. Fresh peptide samples were reconstituted in purifiedwater at 5 mM and diluted into 50 mM HEPES pH 7.4 with 50 mM NaCl to 100nM final concentration. Solid compounds were dissolved in DMSO (10 mM),and then diluted serially in DMSO (300×) followed by dilution in buffer(1×) to provide solutions with a consistent final DMSO concentration of0.33%. Data for compounds tested are presented in Table 1.

TABLE 1 Ex. IC₅₀ (μM)  1 1.4  2 1.2  3 1.1  4 1.5  5 0.9  6 1.1  7 1.2 8 1.2  9 1.0 10 1.0 11 1.6 12 1.5 13 1.2 14 1.4 15 2.2 16 1.2 18 1.4 192.4 20 2.0 22 1.7 23 1.4 24 1.1 63 5.0 64 4.6 66 2.4

Biological Example 2: NMR Assay for Effect of Test Compounds onAlpha-Synuclein Interaction with Lipid Membranes

To measure the interaction of test compounds with full-length ASYN inthe presence of lipid membranes, an NMR assay is conducted. NMRmeasurements are made in 20 mM Phosphate, pH=7.4, 100 mM NaCl on VarianDirect Drive 600 MHz and Varian Inova 800 MHz spectrometers with 10% D₂Oas lock solvent. Spectra are processed using NMRPipe (see F. Delaglio,S. Grzesiek, G. W. Vuister, G. Zhu, J. Pfeifer, A. Bax, J Biomol NMR1995, 6, 277-293). α-Synuclein is used at 0.12 mM while1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG)-liposomes areadded at 0.8 mg/ml where present. All ¹H-¹⁵N correlation spectra arerecorded with a SOFAST pulse sequence (see P. Schanda, E. Kupce, B.Brutscher, J Biomol NMR 2005, 33, 199-211). Resonance assignment at nearphysiological conditions are readily available from a previouspublication (BMRB ID 16300; see J. N. Rao, Y. E. Kim, L. S. Park, T. S.Ulmer, J Mol Biol 2009, 390, 516-529). For ligand titration, the testcompounds are added stepwise to the liposome/ASYN mixture. ¹⁵N-¹Hcorrelation spectra are recorded for each step, and the signalintensities are referenced to the free form of ASYN while accounting fordilution effects. To reduce noise in the available data, the intensityratio for several amide positions of ASYN are averaged for two regionschosen to correspond to the SL1 and SL2 binding modes observedpreviously (see C. R. Bodner, A. S. Maltsev, C. M. Dobson, A. Bax,Biochemistry 2010, 49, 862-871).

The heteronuclear single quantum coherence (HSQC) spectroscopy signalintensity for ASYN is attenuated when ASYN is embedded in lipidmembranes. Reversal of lipid-induced attenuation of the HSQC signal bytest compounds indicates the ability of the test compound to disrupt theassociation of ASYN with lipid membrane. Test compounds may reverse theinteraction of ASYN with1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG) (0.8 mg/mL)liposomes in a concentration-dependent manner. Results for ASYN residues66-76 are also analyzed.

Biological Example 3: Effect of Test Compounds on Annular Oligomers inLipid Membranes

Electron microscopy is used to directly visualize the effect of testcompounds on the formation of ASYN oligomers in lipid membranes. Formvargrids with the lipid monolayer are counterstained with a saturateduranyl acetate solution in 50% EtOH for 25 minutes. The grids are thenfloated on a droplet of 2% bismuth subnitrate for 10 min, and againcarefully rinsed with double distilled water three times and allowed tocompletely dry. Grids are imaged using a Zeiss EM10 transmissionelectron microscope Electron Microscope. From each sample grid, 5-10electron micrographs at 10,000× magnification and 5-10 images at 40,000×are obtained. The best negatives are scanned and analyzed with theImageJ 1.43 program to estimate the numbers of annular oligomers perhigher power field (100×100 nm) (Rasband, W. S., ImageJ, U. S. NationalInstitutes of Health, Bethesda, Md., USA, http://imagej.nih.gov/ij/,1997-2014).

Test compounds that interact with oligomeric and lipid-bound forms ofASYN may do so in a way that reduces the affinity of ASYN oligomers forthe lipid membrane. Compounds can interfere with ASYN oligomerization,the binding of ASYN to lipid membranes, and the formation of annularring-like oligomers (“pores”) in these membranes, which may alter theaggregation of ASYN and prevent the formation of specific oligomericstructures believed to contribute to the neurotoxicity of misfolded,oligomerized ASYN in Parkinson's disease.

Biological Example 4: Effect of Test Compounds on Alpha-Synuclein inCells

The effect of test compounds on the accumulation of ASYN in B103neuroblastoma cells overexpressing human ASYN is studied. A lentiviralexpression system is used to express GFP-tagged ASYN in these cells.Forty-eight hours after expression is initiated, vehicle or testcompound is added for an additional 24 hours. The amount of accumulatedGFP-ASYN is then visualized to determine the reduction in concentrationof ASYN-GFP in the ASYN-overexpressing cells.

Biological Example 5: In Vivo Efficacy Studies

Parkinson's disease (PD) is characterized by aberrant accumulation ofoligomeric forms of alpha-synuclein (ASYN). It is hypothesized thatthese toxic forms of ASYN contribute to the neuronal dysfunction andcell death observed in PD and other synucleinopathies, in part, thoughthe formation of pore-like structures in cell membranes. The compoundsdescribed herein were designed to ameliorate PD-related symptoms andpathology by selectively blocking the formation and accumulation ofthese toxic species of ASYN.

A) Transgenic Mouse Model of Parkinson's Disease. Test compounds areevaluated in a transgenic mouse model of PD overexpressing humanwild-type ASYN under the Thy-1 promoter (also referred to as the Line 61ASYN transgenic mouse), by administering test compounds at 0, 1, or 5mg/kg (i.p.) once daily (five days per week) for three months and thenassessing PD-relevant sensorimotor performance, biochemical alterations,and neuropathological changes in ASYN and related proteins.

The Round Beam Task is used to assess sensorimotor impairments, usingnumber of slips as the primary outcome measure. ASYN transgenic andnon-transgenic mice are tested, and the statistical significance in theincrease in number of slips for vehicle-treated transgenic subjects ascompared to vehicle-treated non-transgenic control subjects iscalculated.

Western Blot analysis of cerebral cortical and hippocampal brainhomogenates is performed, and the statistical significance of thereduction in transgenic ASYN protein levels is calculated. Biochemicalevaluations of oligomeric proteins using A11 antibody dot blot methods(including ASYN) in cortical homogenates are performed.

B) Line 61 ASYN Transgenic Mouse Models. Previous immunolabeling studiesby Masliah and colleagues have demonstrated statistically significantincreases in ASYN immunolabeling in cortical neuropil in the Line 61ASYN transgenic mouse (Masliah E. et al., Science, 2000,287(5456):1265-9). These neuropathological findings can be reconfirmedin the current study using the methods described by Masliah andcolleagues. Neurodegeneration-related markers including tyrosinehydroxylase, NeuN, and GFAP are monitored.

The effect of test compounds at various dosages on sensorimotorimpairment in Line 61 ASYN transgenic mice is studied, using the RoundBeam Motor Performance assay described above, and the statisticalsignificance in the increase in the number of slips in vehicle-treatedASYN transgenic control mice as compared to vehicle-treatednon-transgenic control subjects is calculated. These studies evaluateimprovement in sensorimotor, biochemical, behavioral, andneuropathological outcomes in a transgenic mouse model Parkinson'sdisease/Dementia with Lewy bodies (PD/DLB).

1. A compound of Formula (IA):

wherein B is a 9- or 10-membered heteroaryl, or a 5- or 6-memberedheterocycloalkyl, each unsubstituted or substituted with —(R¹)_(m);wherein m is 0, 1, or 2; and each R¹ is independently C₁₋₄alkyl(optionally substituted with one or more halo or —OC₁₋₄alkyl groups),halo, —OH, or —OC₁₋₄alkyl; R² is H, C₁₋₅alkyl (unsubstituted orsubstituted with one or more halo substituents), —OC₁₋₄alkyl, or—SC₁₋₄alkyl, or an aryl, monocyclic cycloalkyl, or—C₁₋₄alkyl-(monocyclic cycloalkyl) group, wherein each aryl orcycloalkyl is unsubstituted or substituted with halo, C₁₋₄alkyl, orhalo-C₁₋₄alkyl; A is a 5-membered heteroaryl ring; Y is absent or isC₁₋₄alkylene; and when Y is absent or is C₁₋₄alkylene, R³ and R⁴ takentogether with the nitrogen to which they are attached form a monocyclicor bicyclic heterocycloalkyl or

 each unsubstituted or substituted with one or more R^(g) substituents;wherein each R^(g) substituent is independently C₁₋₄alkyl (unsubstitutedor substituted with one or more C₁₋₄alkoxy, halo-C₁₋₄alkoxy, or halogroups), C₃₋₇cycloalkyl, C₁₋₄alkoxy, halo-C₁₋₄alkoxy, or halo; or, whenY is C₁₋₄alkylene, R³ and Y taken together with the nitrogen to which R³is attached form a monocyclic or bicyclic heterocycloalkyl ring, whichring is unsubstituted or substituted with C₁₋₄alkyl or halo; and R⁴ is Hor C₁₋₄alkyl; and R⁵ is H or C₁₋₄alkyl; or a pharmaceutically acceptablesalt thereof.
 2. The compound of claim 1, wherein one or more of thefollowing limitations applies: (a1) m is 1 or 2; or (a2) m is 1 or 2,and R¹ is as defined herein, wherein at least one R¹ is C₁₋₄alkyl(substituted with one or two halo groups, or with —OC₁₋₄alkyl),C₁₋₄alkyl (substituted with —CF₃), —OH, or —OC₁₋₄alkyl; (b) R² isC₁₋₅alkyl substituted with two halo groups, —OC₁₋₄alkyl, or —SC₁₋₄alkyl,or is monocyclic cycloalkyl substituted with halo, C₁₋₄alkyl, orhalo-C₁₋₄alkyl, or is —C₁₋₄alkyl-(monocyclic cycloalkyl), wherein thecycloalkyl is unsubstituted or substituted with halo, C₁₋₄alkyl, orhalo-C₁₋₄alkyl, or is aryl substituted with halo, C₁₋₄alkyl, orhalo-C₁₋₄alkyl; and (c) when R³ and R⁴ taken together with the nitrogento which they are attached form a monocyclic heterocycloalkyl, saidheterocycloalkyl is substituted with one or more R^(g) substituents andR^(g) is as defined herein; and at least one R^(g) substituent isC₁₋₄alkyl (substituted with one or more C₁₋₄alkoxy, halo-C₁₋₄alkoxy, orhalo groups), C₁₋₄alkoxy, halo-C₁₋₄alkoxy, or halo.
 3. The compound ofclaim 1, wherein B is an optionally substituted 9-membered bicyclicheteroaryl.
 4. The compound of claim 1 or 2, wherein B is optionallysubstituted indole, benzofuran, benzothiophene, indazole, benzimidazole,benzoxazole, benzisoxazole, imidazopyridine, or pyrrolopyridine.
 5. Thecompound of claim 1 or 2, wherein B is optionally substituted indole,benzofuran, benzothiophene, indazole, benzisoxazole, imidazopyridine, orpyrrolopyridine.
 6. The compound of claim 1 or 2, wherein B isoptionally substituted indole or is optionally substituted 3-indole. 7.The compound of claim 1 or 2, wherein B is substituted indole orsubstituted 3-indole.
 8. The compound of claim 1 or 2, wherein B is anoptionally substituted 10-membered bicyclic heteroaryl; or is anoptionally substituted monocyclic 5- or 6-membered heterocycloalkyl. 9.The compound of any one of claims 1-8, wherein m is
 0. 10. The compoundof any one of claims 1-8, wherein m is
 1. 11. The compound of any one ofclaims 1-8, wherein m is
 2. 12. The compound of any one of claims 1-11,wherein each R¹ substituent is independently —OH, or is fluoro, chloro,bromo, or iodo.
 13. The compound of claim 12, wherein each R¹ is fluoroor bromo.
 14. The compound of any one of claims 1-11, wherein each R¹substituent is independently methyl, ethyl, propyl, isopropyl, butyl,sec-butyl, isobutyl, tert-butyl, or is C₁₋₄alkyl (substituted with oneor more fluoro, chloro, bromo, methoxy, ethoxy, propoxy, isopropoxy, orbutoxy groups).
 15. The compound of any one of claims 1-11, wherein eachR¹ is independently halo or C₁₋₄alkyl optionally substituted with one ormore halo groups.
 16. The compound of any one of claims 1-11, whereineach R¹ is independently OMe, OCHF₂, OCF₃, OEt, OiPr, Me, CF₃, Cl, orCH₂F, CHF₂.
 17. The compound of any one of claims 1-16, wherein R² is H.18. The compound of any one of claims 1-16, wherein R² is C₁₋₅alkyl(unsubstituted or substituted with one or more halo substituents). 19.The compound of any one of claims 1-16, wherein R² is —OC₁₋₄alkyl or—SC₁₋₄alkyl.
 20. The compound of any one of claims 1-16, wherein R² isC₁₋₅alkyl (substituted with one or more halo substituents).
 21. Thecompound of any one of claims 1-16, wherein R² is unsubstituted orsubstituted C₁₋₅alkyl; or is unsubstituted or substituted C₃₋₅alkyl. 22.The compound of any one of claims 1-16, wherein R² is 1,1-difluorobutyl,trifluoro-isopentyl, trifluorobutyl, 3,3-difluorobutyl,2,2-difluorobutyl, or propoxy.
 23. The compound of any one of claims1-16, wherein R² is monocyclic cycloalkyl or —C₁₋₄alkyl-(monocycliccycloalkyl), wherein each cycloalkyl is unsubstituted or substitutedwith halo, C₁₋₄alkyl, or halo-C₁₋₄alkyl.
 24. The compound of any one ofclaims 1-16, wherein R² is cyclobutyl, cyclopentyl, cyclopentadienyl,cyclohexyl, or cycloheptyl, each optionally substituted with one or twosubstituents selected from the group consisting of methyl, halo, ortrifluoromethyl.
 25. The compound of any one of claims 1-16, wherein R²is substituted monocyclic cycloalkyl or substituted—C₁₋₄alkyl-(monocyclic cycloalkyl).
 26. The compound of any one ofclaims 1-16, wherein R² is cyclopropylethyl, (3-methylcyclobutyl)methyl,or (3,3-difluorocyclobutyl)methyl.
 27. The compound of any one of claims1-16, wherein R² is optionally substituted aryl.
 28. The compound of anyone of claims 1-16, wherein R² is optionally substituted phenyl.
 29. Thecompound of any one of claims 1-16, wherein R² is substituted C₁₋₅alkyl,or substituted monocyclic cycloalkyl, or substituted—C₁₋₄alkyl-(monocyclic cycloalkyl), or substituted phenyl.
 30. Thecompound of any one of claims 1-29, wherein A is pyrrole, furan,thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole, triazole,oxadiazole, thiadiazole, or tetrazole.
 31. The compound of claim 30,wherein A is pyrrole, furan, thiophene, pyrazole, imidazole, oxazole,thiazole, triazole, oxadiazole, thiadiazole, or tetrazole.
 32. Thecompound of claim 30, wherein A is imidazole, oxazole, or thiazole. 33.The compound of claim 30, wherein A is thiazole.
 34. The compound of anyone of claims 1-33, wherein Y is absent.
 35. The compound of any one ofclaims 1-29, wherein Y is —CH₂—, —CH₂CH₂—, —CH(CH₃)—, —(CH₂)₃—,—C(CH₃)₂—, —(CH₂)₄—, —CH((CH₂)₂CH₃)—, —CH(CH(CH₃)₂)—, —CH(CH₂CH₃)CH₂—,—CH(CH₃)CH(CH₃)—, —CH(CH₃)(CH₂)₂—, or —CH₂CH(CH₃)CH₂—.
 36. The compoundof any one of claims 1-29, wherein Y is —CH₂CH₂—.
 37. The compound ofany one of claims 1-29, wherein Y is absent or is C₁₋₄alkylene, and R³and R⁴ taken together with the nitrogen to which they are attached forma monocyclic or bicyclic heterocycloalkyl ring, unsubstituted orsubstituted with one or more R^(g) substituents.
 38. The compound ofclaim 37, wherein R³ and R⁴ taken together with the nitrogen to whichthey are attached form azetidine, pyrrolidine, piperidine, piperazine,morpholine, thiomorpholine, 1,1-dioxo-thiomorpholine, azepine, ordiazepine, each unsubstituted or substituted with one or more R^(g)substituents.
 39. The compound of claim 37, wherein R³ and R⁴ takentogether with the nitrogen to which they are attached form piperidine,piperazine, or diazepine, each unsubstituted or substituted with one ormore R^(g) substituents.
 40. The compound of claim 37, wherein R³ and R⁴taken together with the nitrogen to which they are attached formpiperazine substituted with one, two, or three R^(g) substituents. 41.The compound of claim 37, wherein R³ and R⁴ taken together with thenitrogen to which they are attached form piperazine, unsubstituted orsubstituted with C₁₋₄alkyl.
 42. The compound of claim 37, wherein R³ andR⁴ taken together with the nitrogen to which they are attached form amonocyclic heterocycloalkyl ring, unsubstituted or substituted with oneor more R^(g) substituents, and Y is absent or Y is C₂₋₄alkylene. 43.The compound of any one of claims 1-42, wherein each R^(g) substituentis independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, or is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, or is methoxy, ethoxy, propoxy, or isopropoxy, or istrifluoromethoxy or trifluoroethoxy, or is bromo, chloro, or fluoro,each unsubstituted or substituted.
 44. The compound of any one of claims1-42, wherein each R^(g) substituent is independently ethyl, isopropyl,cyclopropyl, tert-butyl, isobutyl, 2-methoxyethyl, 2,2-difluoroethyl,trifluoroethyl, trifluoroethoxy-ethyl, trifluoromethyl, difluoromethyl,or fluoromethyl.
 45. The compound of any one of claims 1-42, whereinthere are 0, 1, 2, or 3 R^(g) substituents.
 46. The compound of any oneof claims 1-42, wherein there is 1 R^(g) substituent, or there are 2R^(g) substituents, or there are 3 R^(g) substituents.
 47. The compoundof any one of claims 1-33, wherein Y is C₁₋₄alkylene, and R³ and Y aretaken together with the nitrogen to which R³ is attached form amonocyclic heterocycloalkyl ring, which ring is unsubstituted orsubstituted with C₁₋₄alkyl or halo; and R⁴ is H or C₁₋₄alkyl.
 48. Thecompound of any one of claims 1-42, wherein R³ and R⁴ taken togetherwith the nitrogen to which they are attached form a monocyclicheterocycloalkyl ring, substituted with one or more R^(g) substituents;wherein R^(g) is as defined in claim 1; and at least one R^(g)substituent is C₁₋₄alkyl (substituted with one or more C₁₋₄alkoxy,halo-C₁₋₄alkoxy, or halo groups), C₁₋₄alkoxy, halo-C₁₋₄alkoxy, or halo.49. The compound of claim 1, which is a compound of Formula (II):

wherein B′ is a 5-membered heteroaryl; B″ is phenyl or a 6-memberedheteroaryl; and R¹, R², R³, R⁴, R⁵, m, A, and Y are as defined in anyone of the preceding claims; or a pharmaceutically acceptable saltthereof.
 50. The compound of claim 1, which is a compound of Formula(III):

wherein B′ is a 5-membered heteroaryl; B″ is phenyl or a 6-memberedheteroaryl; and R¹, R², R³, R⁴, R⁵, m, and Y are as defined in any oneof the preceding claims; or a pharmaceutically acceptable salt thereof.51. The compound according to any one of the preceding claims, which isnot:

or a pharmaceutically acceptable salt thereof.
 52. A compound selectedfrom the group consisting of:

and pharmaceutically acceptable salts thereof.
 53. A compound selectedfrom the group consisting of:

or a pharmaceutically acceptable salt thereof.
 54. A compound selectedfrom the group consisting of the compounds in List 1, andpharmaceutically acceptable salts thereof.
 55. A pharmaceuticalcomposition comprising at least one compound according to any one of thepreceding claims, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient.
 56. A method of treating aneurodegenerative disease or condition associated with protein orpeptide aggregation, comprising administering to a subject in need ofsuch treatment an effective amount of at least one compound according toany one of claims 1-54, or a pharmaceutically acceptable salt thereof,or a pharmaceutical composition according to claim
 55. 57. A method ofinterfering with the accumulation of protein or peptide aggregates in acell, or preventing, slowing, reversing, or inhibiting protein orpeptide aggregation in a cell, comprising contacting the cell with aneffective amount of at least one compound according to any one of claims1-54, or a pharmaceutically acceptable salt thereof, and/or with apharmaceutical composition according to claim 55, wherein the contactingis in vitro, ex vivo, or in vivo.